Piperidino pyrimidine dipeptidyl peptidase inhibitors for the treatment of diabetes

ABSTRACT

The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/US03/21758 filed 11 Jul. 2003, which claims the benefit under 35U.S.C. 119(e) of U.S. Provisional Application No. 60/395,846, filed 15Jul. 2002.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Often abnormal glucose homeostasis is associated bothdirectly and indirectly with alterations of the lipid, lipoprotein andapolipoprotein metabolism and other metabolic and hemodynamic disease.Therefore patients with Type 2 diabetes mellitus are at especiallyincreased risk of macrovascular and microvascular complications,including coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Therefore,therapeutical control of glucose homeostasis, lipid metabolism andhypertension are critically important in the clinical management andtreatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), patientsproduce little or no insulin, the hormone which regulates glucoseutilization. In Type 2 diabetes, or noninsulin dependent diabetesmellitus (NIDDM), patients often have plasma insulin levels that are thesame or even elevated compared to nondiabetic subjects; however, thesepatients have developed a resistance to the insulin stimulating effecton glucose and lipid metabolism in the main insulin-sensitive tissues,which are muscle, liver and adipose tissues, and the plasma insulinlevels, while elevated, are insufficient to overcome the pronouncedinsulin resistance.

Insulin resistance is not primarily due to a diminished number ofinsulin receptors but to a post-insulin receptor binding defect that isnot yet understood. This resistance to insulin responsiveness results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue and of glucose production and secretion in the liver.

The available treatments for Type 2 diabetes, which have not changedsubstantially in many years, have recognized limitations. While physicalexercise and reductions in dietary intake of calories will dramaticallyimprove the diabetic condition, compliance with this treatment is verypoor because of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic β-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate the very insulin-resistant tissues. However, dangerously lowlevels of plasma glucose can result from administration of insulin orinsulin secretagogues (sulfonylureas or meglitinide), and an increasedlevel of insulin resistance due to the even higher plasma insulin levelscan occur. The biguanides increase insulin sensitivity resulting in somecorrection of hyperglycemia. However, the two biguanides, phenformin andmetformin, can induce lactic acidosis and nausea/diarrhea. Metformin hasfewer side effects than phenformin and is often prescribed for thetreatment of Type 2 diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a morerecently described class of compounds with potential for amelioratingmany symptoms of Type 2 diabetes. These agents substantially increaseinsulin sensitivity in muscle, liver and adipose tissue in severalanimal models of Type 2 diabetes resulting in partial or completecorrection of the elevated plasma levels of glucose without occurrenceof hypoglycemia. The glitazones that are currently marketed are agonistsof the peroxisome proliferator activated receptor (PPAR), primarily thePPAR-gamma subtype. PPAR-gamma agonism is generally believed to beresponsible for the improved insulin sensititization that is observedwith the glitazones. Newer PPAR agonists that are being tested fortreatment of Type 2 diabetes are agonists of the alpha, gamma or deltasubtype, or a combination of these, and in many cases are chemicallydifferent from the glitazones (i.e., they are not thiazolidinediones).Serious side effects (e.g. liver toxicity) have occurred with some ofthe glitazones, such as troglitazone.

Additional methods of treating the disease are still underinvestigation. New biochemical approaches that have been recentlyintroduced or are still under development include treatment withalpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosinephosphatase-1B (PTP-1B) inhibitors.

Compounds that are inhibitors of the dipeptidyl peptidase-IV (“DP-IV” or“DPP-IV”) enzyme are also under investigation as drugs that may beuseful in the treatment of diabetes, and particularly Type 2 diabetes.See for example WO 97/40832; WO 98/19998; U.S. Pat. No. 5,939,560;Bioorg. Med. Chem. Lett., 6(10), 1163–1166 (1996); and Bioorg. Med.Chem. Lett., 6(22), 2745–2748 (1996). The usefulness of DP-IV inhibitorsin the treatment of Type 2 diabetes is based on the fact that DP-IV invivo readily inactivates glucagon like peptide-1 (GLP-1) and gastricinhibitory peptide (GIP). GLP-1 and GIP are incretins and are producedwhen food is consumed. The incretins stimulate production of insulin.Inhibition of DP-IV leads to decreased inactivation of the incretins,and this in turn results in increased effectiveness of the incretins instimulating production of insulin by the pancreas. DP-IV inhibitiontherefore results in an increased level of serum insulin.Advantageously, since the incretins are produced by the body only whenfood is consumed, DP-IV inhibition is not expected to increase the levelof insulin at inappropriate times, such as between meals, which can leadto excessively low blood sugar (hypoglycemia). Inhibition of DP-IV istherefore expected to increase insulin without increasing the risk ofhypoglycemia, which is a dangerous side effect associated with the useof insulin secretagogues.

DP-IV inhibitors also have other therapeutic utilities, as discussedherein. DP-IV inhibitors have not been studied extensively to date,especially for utilities other than diabetes. New compounds are neededso that improved DP-IV inhibitors can be found for the treatment ofdiabetes and potentially other diseases and conditions.

SUMMARY OF THE INVENTION

The present invention is directed to compounds which are inhibitors ofthe dipeptidyl peptidase-IV enzyme (“DP-IV inhibitors”) and which areuseful in the treatment or prevention of diseases in which thedipeptidyl peptidase-IV enzyme is involved, such as diabetes andparticularly Type 2 diabetes. The invention is also directed topharmaceutical compositions comprising these compounds and the use ofthese compounds and compositions in the prevention or treatment of suchdiseases in which the dipeptidyl peptidase-IV enzyme is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   Ar is phenyl which is unsubstituted or substituted with 1–5 of R³,    wherein R³ is independently selected from the group consisting of:    -   (1) halogen,    -   (2) C₁₋₆alkyl, which is linear or branched and is unsubstituted        or substituted with 1–5 halogens,    -   (3) OC₁₋₆alkyl, which is linear or branched and is unsubstituted        or substituted with 1–5 halogens,    -   (4) CN, and    -   (5) OH;-   R¹ and R² are independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) CN,    -   (3) C₁₋₁₀alkyl, which is linear or branched and which is        unsubstituted or substituted with:        -   (a) halogen, or        -   (b) phenyl, which is unsubstituted or substituted with 1–5            substituents independently selected from halogen, CN, OH,            R⁴, OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁷R⁸, NR⁷R⁸,            CONR⁷R⁸, CO₂H, and CO₂C₁₋₆alkyl, wherein the C₁₋₆alkyl is            linear or branched,    -   (4) phenyl which is unsubstituted or substituted with 1–5        substituents independently selected from halogen, CN, OH, R⁴,        OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁷R⁸, NR⁷R⁸,        CONR⁷R⁸, CO₂H, and CO₂C₁₋₆alkyl, wherein the C₁₋₆alkyl is linear        or branched,    -   (5) a 5- or 6-membered heterocycle which may be saturated or        unsaturated comprising 1–4 heteroatoms independently selected        from N, S and O, the heterocycle being unsubstituted or        substituted with 1–3 substituents independently selected from        oxo, halogen, NO₂, CN, OH, R⁴, OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴,        SO₂R⁴, SO₂NR⁷R⁸, NR⁷R⁸, CONR⁷R⁸, CO₂H, and CO₂C₁₋₆alkyl, wherein        the C₁₋₆alkyl is linear or branched,    -   (6) C₃₋₆cycloalkyl, which is optionally substituted with 1–5        substituents independently selected from halogen, OH, C₁₋₆alkyl,        and OC₁₋₆alkyl, wherein the C₁₋₆alkyl and OC₁₋₆alkyl are linear        or branched and optionally substituted with 1–5 halogens,    -   (7) OH,    -   (8) OR⁴, and    -   (9) NR⁷R⁸;-   R⁴ is C₁₋₆alkyl, which is linear or branched and which is    unsubstituted or substituted with 1–5 groups independently selected    from halogen, CO₂H, and CO₂C₁₋₆alkyl, wherein the C₁₋₆alkyl is    linear or branched;-   R⁵, R⁶ and R⁹ are independently selected from the group consisting    of:    -   (1) hydrogen,    -   (2) C₁₋₁₀alkyl, which is linear or branched and which is        unsubstituted or substituted with one or more substituents        selected from:        -   (a) halogen,        -   (b) hydroxy,        -   (c) phenyl, which is unsubstituted or substituted with 1–5            substituents independently selected from halogen, OH,            C₁₋₆alkyl, and OC₁₋₆alkyl, wherein the C₁₋₆alkyl is linear            or branched and optionally substituted with 1–5 halogens,        -   (d) naphthyl, wherein the naphthyl is optionally substituted            with 1–5 substituents independently selected from halogen,            OH, C₁₋₆alkyl, and OC₁₋₆alkyl, wherein the C₁₋₆alkyl is            linear or branched and optionally substituted with 1–5            halogens,        -   (e) CO₂H,        -   (f) CO₂C₁₋₆alkyl,        -   (g) CONR⁷R⁸,    -   (3) CN,    -   (4) phenyl which is unsubstituted or substituted with 1–5        substituents independently selected from C₁₋₆alkyl, OC₁₋₆alkyl,        hydroxy and halogen, wherein the C₁₋₆alkyl is linear or branched        and optionally substituted with 1–5 halogens,    -   (5) naphthyl which is unsubstituted or substituted with 1–5        substituents independently selected from C₁₋₆alkyl, OC₁₋₆alkyl,        hydroxy and halogen, wherein the C₁₋₆alkyl is linear or branched        and optionally substituted with 1–5 halogens,    -   (6) CO₂H,    -   (7) CO₂C₁₋₆alkyl,    -   (8) CONR⁷R⁸, and    -   (9) C₃₋₆cycloalkyl, which is unsubstituted or substituted with        1–5 substituents independently selected from halogen, OH,        C₁₋₆alkyl, and OC₁₋₆alkyl, wherein the C₁₋₆alkyl is linear or        branched and optionally substituted with 1–5 halogens;-   R⁷ and R⁸ are independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) phenyl, which is unsubstituted or substituted with        substituents independently selected from halogen, OH, C₁₋₆alkyl,        and OC₁₋₆alkyl, wherein the C₁₋₆alkyl is linear or branched and        optionally substituted with 1–5 halogens,    -   (3) C₃₋₆cycloalkyl, which is unsubstituted or substituted with        substituents independently selected from halogen, OH, C₁₋₆alkyl,        and OC₁₋₆alkyl, wherein the C₁₋₆alkyl is linear or branched and        optionally substituted with 1–5 halogens, and    -   (4) C₁₋₆alkyl, which is linear or branched and which is        unsubstituted or substituted with:        -   (a) halogen, or        -   (b) phenyl, which is unsubstituted or substituted with 1–5            substituents independently selected from halogen, OH,            C₁₋₆alkyl, and OC₁₋₆alkyl, wherein the C₁₋₆alkyl is linear            or branched and optionally substituted with 1–5 halogens,    -   or wherein R⁷ and R⁸ together with the nitrogen atom to which        they are attached form a heterocyclic ring selected from        azetidine, pyrrolidine, piperidine, piperazine, and morpholine        wherein said heterocyclic ring is unsubstituted or substituted        with one to five substituents independently selected from        halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are unsubstituted or substituted with one to five        halogens;        and pharmaceutically acceptable salts thereof and individual        diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein Ar, R¹, R², R⁵, R⁶ and R⁹ are defined herein;and pharmaceutically acceptable salts and individual diastereomersthereof.

Another embodiment of the present invention includes compounds of theformula Ib:

wherein Ar, R¹, R² and R⁵ are defined herein;and pharmaceutically acceptable salts and individual diastereomersthereof.

Another embodiment of the present invention includes compounds of theformula Ic:

wherein Ar, R¹ and R⁵ are defined herein;and pharmaceutically acceptable salts thereof and individualdiastereomers thereof.

Another embodiment of the present invention includes compounds of theformula Id:

wherein Ar and R¹ are defined herein;and pharmaceutically acceptable salts and individual diastereomersthereof.

Another embodiment of the present invention includes compounds of theformula Ie:

wherein Ar, R¹ and R² are defined herein;and pharmaceutically acceptable salts and individual diastereomersthereof.

In the present invention it is preferred that Ar is phenyl which isunsubstituted or substituted with 1–5 of R³ which are independentlyselected from the group consisting of:

-   -   (1) fluoro,    -   (2) chloro,    -   (3) bromo,    -   (4) methyl,    -   (5) CF₃, and    -   (6) OH.

In the present invention it is more preferred that Ar is selected fromthe group consisting of:

-   -   (1) phenyl,    -   (2) 2-fluorophenyl,    -   (3) 3,4-difluorophenyl,    -   (4) 2,5-difluorophenyl, and    -   (5) 2,4,5-trifluorophenyl.

In the present invention it is preferred that R¹ is selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) C₁₋₆alkyl, which is linear or branched and which is        unsubstituted or substituted with phenyl or 1–5 fluoro,    -   (3) phenyl which is unsubstituted or substituted with 1–5        substituents independently selected from halogen, CN, OH, R⁴,        OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁷R⁸, NR⁷R⁸,        CONR⁷R⁸, CO₂H, and CO₂C₁₋₆alkyl, wherein the C₁₋₆alkyl is linear        or branched,    -   (4) a 5- or 6-membered heterocycle which may be saturated or        unsaturated comprising 14 heteroatoms independently selected        from N, S and O, the heterocycle being unsubstituted or        substituted with 1–3 substituents independently selected from        oxo, halogen, NO₂, CN, OH, R⁴, OR⁴, NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴,        SO₂R⁴, SO₂NR⁷R⁸, NR⁷R⁸, CONR⁷R⁸, CO₂H, and CO₂C₁₋₆alkyl, wherein        the C₁₋₆alkyl is linear or branched,    -   (5) C₃₋₆cycloalkyl, and    -   (6) NR⁷R⁸.

In the present invention it is more preferred that R¹ is selected fromthe group consisting of:

-   -   (1) hydrogen,    -   (2) CF₃,    -   (3) phenyl which is unsubstituted or substituted with 1–5        substituents independently selected from halogen, methyl, CF₃,        OCF₃, NHSO₂Me, NHSO₂CF₃, SO₂Me, SO₂CF₃, SO₂NH₂, NH₂, NHMe, NMe₂,        and CONH₂,    -   (4) pyridine, pyrazine, and imidazole which is unsubstituted or        substituted with 1–5 substituents independently selected from        CF₃, Me, and NO₂,    -   (5) cyclopropyl,    -   (6) morpholine,    -   (7) NH₂,    -   (8) NHMe,    -   (9) NMe₂, and    -   (10) NHCH₂Ph.

In the present invention it is more preferred that R¹ is selected fromthe group consisting of:

-   -   (1) hydrogen,    -   (2) CF₃,    -   (3) phenyl which is unsubstituted or substituted with 1–5        substituents independently selected from halogen, methyl, CF₃,        OCF₃, NHSO₂Me, SO₂Me, SO₂CF₃, SO₂NH₂, and CONH₂,    -   (4) pyridine, pyrazine, or imidazole which is unsubstituted or        substituted with 1–5 substituents independently selected from        CF₃, Me, and NO₂, and    -   (5) cyclopropyl.

In the present invention it is even more preferred that R¹ is hydrogenOr CF₃.

In the present invention it is preferred that R² is selected from:

-   -   (1) hydrogen,    -   (2) C₁₋₆alkyl, which is linear or branched and which is        unsubstituted or substituted with 1–5 fluoro,    -   (3) OH,    -   (4) OR⁴, and    -   (5) NR⁷R⁸.

In the present invention it is more preferred that R² is selected fromthe group consisting of:

-   -   (1) hydrogen,    -   (2) OH,    -   (3) methoxy,    -   (4) isopropoxy,    -   (5) CF₃,    -   (6) NH₂, and    -   (7) NHMe.

In the present invention it is even more preferred that R² is hydrogen.

In the present invention it is preferred that R⁵, R⁶ and R⁹ areindependently selected from the group consisting of:

-   -   (1) hydrogen and    -   (2) C₁₋₁₀alkyl, which is linear or branched and which is        unsubstituted or substituted with one or more substituents        selected from:        -   (a) halogen, and        -   (b) phenyl, wherein the phenyl is optionally substituted            with 1–5 substituents independently selected from halogen,            OH, C₁₋₆alkyl, and OC₁₋₆alkyl, wherein the C₁₋₆alkyl and            OC₁₋₆alkyl are linear or branched and optionally substituted            with 1–5 halogens.

In the present invention it is more preferred that R⁵, R⁶ and R⁹ areindependently selected from the group consisting of:

-   -   (1) hydrogen,    -   (2) CH₃, and    -   (3) CH₂-phenyl.

In the present invention it is even more preferred that R⁵ is H or CH₃and R⁶ and R⁹ are hydrogen.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. The compounds of the instant invention have oneasymmetric center at the beta carbon atom. Additional asymmetric centersmay be present depending upon the nature of the various substituents onthe molecule. Each such asymmetric center will independently produce twooptical isomers and it is intended that all of the possible opticalisomers and diastereomers in mixtures and as pure or partially purifiedcompounds are included within the ambit of this invention. The presentinvention is meant to comprehend all such isomeric forms of thesecompounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention.

Formula I shows the structure of the class of compounds withoutpreferred stereochemistry. Formula Ia shows the preferredstereochemistry at the carbon atom that is attached to the amino groupof the beta amino acid from which these compounds are prepared.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, fumaric, and tartaric acids.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

As appreciated by those of skill in the art, halo or halogen as usedherein is intended to include fluoro, chloro, bromo and iodo. Similarly,C₁₋₆, as in C₁₋₆alkyl is defined to identify the group as having 1, 2,3, 4, 5 or 6 carbons in a linear or branched arrangement, such thatC₁₋₆alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. Likewise, C₀, as inC₀alkyl is defined to identify the presence of a direct covalent bond. Agroup which is designated as being independently substituted withsubstituents may be independently substituted with multiple numbers ofsuch substituents. The term “heterocycle” as used herein is intended toinclude 5- to 10-membered ring systems which are within the followinglisting: benzimidazolyl, benzodioxanyl, benzofuranyl, benzopyrazolyl,benzothiadiazolyl, benzotriazolyl, benzothiophenyl, benzoxadiazolyl,benzoxazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, furanyl,imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl,isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl,thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl,piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxyphenyl, tetrahydrofuranyl, tetrahydroimidazolyl,tetrahydroisoquinolinyl, and tetrahydrothienyl.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein.

Specific compounds within the present invention include a compound whichis selected from the group consisting of the compounds disclosed in thefollowing Examples and pharmaceutically acceptable salts thereof andindividual diastereomers thereof.

The subject compounds are useful in a method of inhibiting thedipeptidyl peptidase-IV enzyme in a patient such as a mammal in need ofsuch inhibition comprising the administration of an effective amount ofthe compound. The present invention is directed to the use of thecompounds disclosed herein as inhibitors of dipeptidyl peptidase-IVenzyme activity.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

The present invention is further directed to a method for themanufacture of a medicament for inhibiting dipeptidyl peptidase-IVenzyme activity in humans and animals comprising combining a compound ofthe present invention with a pharmaceutical carrier or diluent.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom inhibition ofdipeptidyl peptidase-IV enzyme activity is desired. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician. As used herein, theterm “treatment” refers both to the treatment and to the prevention orprophylactic therapy of the mentioned conditions.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asinhibitors of dipeptidyl peptidase-IV enzyme activity may bedemonstrated by methodology known in the art. Inhibition constants aredetermined as follows. A continuous fluorometric assay is employed withthe substrate Gly-Pro-AMC, which is cleaved by DP-IV to release thefluorescent AMC leaving group. The kinetic parameters that describe thisreaction are as follows: K_(m)=50 μM; k_(cat)=75 s⁻¹;k_(cat)/K_(m)=1.5×10⁶ M⁻¹s⁻¹. A typical reaction contains approximately50 pM enzyme, 50 μM Gly-Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1mg/ml BSA) in a total reaction volume of 100 μL. Liberation of AMC ismonitored continuously in a 96-well plate fluorometer using anexcitation wavelength of 360 nm and an emission wavelength of 460 nm.Under these conditions, approximately 0.8 μM AMC is produced in 30minutes at 25 degrees C. The enzyme used in these studies was soluble(transmembrane domain and cytoplasmic extension excluded) human proteinproduced in a baculovirus expression system (Bac-To-Bac, Gibco BRL). Thekinetic constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found tobe in accord with literature values for the native enzyme. To measurethe dissociation constants for compounds, solutions of inhibitor in DMSOwere added to reactions containing enzyme and substrate (final DMSOconcentration is 1%). All experiments were conducted at room temperatureusing the standard reaction conditions described above. To determine thedissociation constants (K_(i)), reaction rates were fit by non-linearregression to the Michaelis-Menton equation for competitive inhibition.The errors in reproducing the dissociation constants are typically lessthan two-fold.

In particular, the compounds of the following examples had activity ininhibiting the dipeptidyl peptidase-IV enzyme in the aforementionedassays, generally with an IC₅₀ of less than about 1 μM. Such a result isindicative of the intrinsic activity of the compounds in use asinhibitors of the dipeptidyl peptidase-IV enzyme activity.

Dipeptidyl peptidase-IV enzyme (DP-IV) is a cell surface protein thathas been implicated in a wide range of biological functions. It has abroad tissue distribution (intestine, kidney, liver, pancreas, placenta,thymus, spleen, epithelial cells, vascular endothelium, lymphoid andmyeloid cells, serum), and distinct tissue and cell-type expressionlevels. DP-IV is identical to the T cell activation marker CD26, and itcan cleave a number of immunoregulatory, endocrine, and neurologicalpeptides in vitro. This has suggested a potential role for thispeptidase in a variety of disease processes in humans or other species.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of one ormore of the following conditions or diseases: (1) hyperglycemia, (2) lowglucose tolerance, (3) insulin resistance, (4) obesity, (5) lipiddisorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridernia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), (25) Type 2 diabetes,(26) growth hormone deficiency, (27) neutropenia, (28) neuronaldisorders, (29) tumor metastasis, (30) benign prostatic hypertrophy,(32) gingivitis, (33) hypertension, (34) osteoporosis, and otherconditions that may be treated or prevented by inhibition of DP-IV.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reducation of risk of the diseases,disorders and conditions noted herein.

-   Type 2 Diabetes and Related Disorders: It is well established that    the incretins GLP-1 and GIP are rapidly inactivated in vivo by    DP-IV. Studies with DP-IV^((−/−))-deficient mice and preliminary    clinical trials indicate that DP-IV inhibition increases the steady    state concentrations of GLP-1 and GIP, resulting in improved glucose    tolerance. By analogy to GLP-1 and GIP, it is likely that other    glucagon family peptides involved in glucose regulation are also    inactivated by DP-IV (eg. PACAP). Inactivation of these peptides by    DP-IV may also play a role in glucose homeostasis. The DP-IV    inhibitors of the present invention therefore have utility in the    treatment, prevention, amelioration, control or reduction of the    risk of Type 2 diabetes and in the treatment, prevention,    amelioration, control or reduction of the risk of the numerous    conditions that often accompany Type 2 diabetes, including metabolic    syndrome X, reactive hypoglycemia, and diabetic dyslipidemia.    Obesity, discussed below, is another condition that is often found    with Type 2 diabetes that may respond to treatment with the    compounds of this invention.

The following diseases, disorders and conditions are related to Type 2diabetes, and therefore may be treated, controlled, ameliorated orprevented, by administering the compounds of this invention: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), and other disorderswhere insulin resistance is a component.

-   Obesity: DP-IV inhibitors may be useful for the treatment of    obesity. This is based on the observed inhibitory effects on food    intake and gastric emptying of GLP-1 and GLP-2. Exogenous    administration of GLP-1 in humans significantly decreases food    intake and slows gastric emptying (Am. J. Physiol. 277, R910–R916    (1999)). ICV administration of GLP-1 in rats and mice also has    profound effects on food intake (Nature Medicine 2, 1254–1258    (1996)). This inhibition of feeding is not observed in    GLP-1R^((−/−)) mice, indicating that these effects are mediated    through brain GLP-1 receptors. By analogy to GLP-1, it is likely    that GLP-2 is also regulated by DP-IV. ICV administration of GLP-2    also inhibits food intake, analogous to the effects observed with    GLP-1 (Nature Medicine 6, 802–807 (2000)).-   Growth Hormone Deficiency: DP-IV inhibition may be useful for the    treatment of growth hormone deficiency, based on the hypothesis that    growth-hormone releasing factor (GRF), a peptide that stimulates    release of growth hormone from the anterior pituitary, is cleaved by    the DP-IV enzyme in vivo (WO 00/56297). The following data provide    evidence that GRF is an endogenous substrate: (1) GRF is efficiently    cleaved in vitro to generate the inactive product GRF[3-44] (BBA    1122, 147–153 (1992)); (2) GRF is rapidly degraded in plasma to    GRF[3-44]; this is prevented by the DP-IV inhibitor diprotin A;    and (3) GRF[3-44] is found in the plasma of a human GRF transgenic    pig (J. Clin. Invest. 83, 1533–1540 (1989)). Thus DP-IV inhibitors    may be useful for the same spectrum of indications which have been    considered for growth hormone secretagogues.-   Intestinal Injury: The potential for using DP-IV inhibitors for the    treatment of intestinal injury is suggested by the results of    studies indicating that glucagon-like peptide-2 (GLP-2), a likely    endogenous substrate for DP-IV, may exhibit trophic effects on the    intestinal epithelium (Regulatory Peptides 90, 27–32 (2000)).    Administration of GLP-2 results in increased small bowel mass in    rodents and attenuates intestinal injury in rodent models of colitis    and enteritis.-   Immunosuppression: DP-IV inhibition may be useful for modulation of    the immune response, based upon studies implicating the DP-IV enzyme    in T cell activation and in chemokine processing, and efficacy of    DP-IV inhibitors in in vivo models of disease. DP-IV has been shown    to be identical to CD26, a cell surface marker for activated immune    cells. The expression of CD26 is regulated by the differentiation    and activation status of immune cells. It is generally accepted that    CD26 functions as a co-stimulatory molecule in in vitro models of T    cell activation. A number of chemokines contain proline in the    penultimate position, presumably to protect them from degradation by    non-specific aminopeptidases. Many of these have been shown to be    processed in vitro by DP-IV. In several cases (RANTES, LD78-beta,    MDC, eotaxin, SDF-1alpha), cleavage results in an altered activity    in chemotaxis and signaling assays. Receptor selectivity also    appears to be modified in some cases (RANTES). Multiple N-terminally    truncated forms of a number of chemokines have been identified in in    vitro cell culture systems, including the predicted products of    DP-IV hydrolysis.

DP-IV inhibitors have been shown to be efficacious immunosupressants inanimal models of transplantation and arthritis. Prodipine(Pro-Pro-diphenyl-phosphonate), an irreversible inhibitor of DP-IV, wasshown to double cardiac allograft survival in rats from day 7 to day 14(Transplantation 63, 1495–1500 (1997)). DP-IV inhibitors have beentested in collagen and alkyldiamine-induced arthritis in rats and showeda statistically significant attenuation of hind paw swelling in thismodel (Int. J. Immunopharmacology 19, 15–24 (1997), Immunopharmacology40, 21–26 (1998)). DP-IV is upregulated in a number of autoimmunediseases including rheumatoid arthritis, multiple sclerosis, Graves'disease, and Hashimoto's thyroiditis Immunology Today 20, 367–375(1999)).

-   HIV Infection: DP-IV inhibition may be useful for the treatment or    prevention of HIV infection or AIDS because a number of chemokines    which inhibit HIV cell entry are potential substrates for DP-IV    Immunology Today 20, 367–375 (1999)). In the case of SDF-1alpha,    cleavage decreases antiviral activity (PNAS 95, 6331–6 (1998)).    Thus, stabilization of SDF-1alpha through inhibition of DP-IV would    be expected to decrease HIV infectivity.-   Hematopoiesis: DP-IV inhibition may be useful for the treatment or    prevention of hematopiesis because DP-IV may be involved in    hematopoiesis. A DP-IV inhibitor, Val-Boro-Pro, stimulated    hematopoiesis in a mouse model of cyclophosphamide-induced    neutropenia (WO 99/56753).-   Neuronal Disorders: DP-IV inhibition may be useful for the treatment    or prevention of various neuronal or psychiatric disorders because a    number of peptides implicated in a variety of neuronal processes are    cleaved in vitro by DP-IV. A DP-IV inhibitor thus may have a    therapeutic benefit in the treatment of neuronal disorders.    Endomorphin-2, beta-casomorphin, and substance P have all been shown    to be in vitro substrates for DP-IV. In all cases, in vitro cleavage    is highly efficient, with k_(cat)/K_(m)˜10⁶ M⁻¹s⁻¹ or greater. In an    electric shock jump test model of analgesia in rats, a DP-IV    inhibitor showed a significant effect that was independent of the    presence of exogenous endomorphin-2 (Brain Research 815, 278–286    (1999)).-   Tumor Invasion and Metastasis: DP-IV inhibition may be useful for    the treatment or prevention of tumor invasion and metastasis because    an increase or decrease in expression of several ectopeptidases    including DP-IV has been observed during the transformation of    normal cells to a malignant phenotype (J. Exp. Med. 190, 301–305    (1999)). Up- or down-regulation of these proteins appears to be    tissue and cell-type specific. For example, increased CD26/DP-IV    expression has been observed on T cell lymphoma, T cell acute    lymphoblastic leukemia, cell-derived thyroid carcinomas, basal cell    carcinomas, and breast carcinomas. Thus, DP-IV inhibitors may have    utility in the treatment of such carcinomas.-   Benign Prostatic Hypertrophy: DP-IV inhibition may be useful for the    treatment of benign prostatic hypertrophy because increased DP-IV    activity was noted in prostate tissue from patients with BPH our. J.    Clin. Chem. Clin. Biochem. 30, 333–338 (1992)).-   Sperm motility/male contraception: DP-IV inhibition may be useful    for the altering sperm motility and for male contraception because    in seminal fluid, prostatosomes, prostate derived organelles    important for sperm motility, possess very high levels of DP-IV    activity (Our. J. Clin. Chem. Clin. Biochem 30, 333–338 (1992)).-   Gingivitis: DP-IV inhibition may be useful for the treatment of    gingivitis because DP-IV activity was found in gingival crevicular    fluid and in some studies correlated with periodontal disease    severity (Arch. Oral Biol. 37, 167–173 (1992)).-   Osteoporosis: DP-IV inhibition may be useful for the treatment or    prevention of osteoporosis because GIP receptors are present in    osteoblasts.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapy mayalso includes therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(a) other dipeptidyl peptidase IV (DP-IV) inhibitors;

(b) insulin sensitizers including ligands for PPAR receptors (alphaand/or gamma and/or beta-delta) which have activity as agonists,antagonists, selective activators, or partial agonists, including (i)PPARγ agonists such as the glitazones (e.g. troglitazone, pioglitazone,englitazone, MCC-555, rosiglitazone, and the like) and other PPARligands, including PPARα/γ dual agonists, such as KRP-297, PPARαagonists such as fenofibric acid derivatives (gemfibrozil, clofibrate,fenofibrate and bezafibrate), and PPARγ partial agonists, (ii)biguanides such as metformin and phenformin, and (iii) protein tyrosinephosphatase-1B (PTP-1B) inhibitors;

(c) insulin or insulin mimetics;

(d) sulfonylureas and other insulin secretagogues such as tolbutamideand glipizide, meglitinide, and related materials;

(e) α-glucosidase inhibitors (such as acarbose);

(f) glucagon receptor antagonists such as those disclosed in WO98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;

(g) GLP-1, GLP-1 mimetics, GLP-1 receptor agonists, and exendins such asthose disclosed in WO00/42026 and WO00/59887;

(h) GIP and GIP mimetics such as those disclosed in WO00/58360, and GIPreceptor agonists;

(i) PACAP, PACAP mimetics, and PACAP receptor agonists such as thosedisclosed in WO 01/23420;

(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rivastatin, itavastatin, rosuvastatin, and other statins), (ii)sequestrants (cholestyramine, colestipol, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) nicotinyl alcohol,nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(v) PPARα/γ dual agonists, such as KRP-297, (vi) inhibitors ofcholesterol absorption, such as beta-sitosterol and ezetimibe, (vii)acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe, and(viii) anti-oxidants, such as probucol;

(k) PPARδ agonists, such as those disclosed in WO97/28149;

(l) antiobesity compounds such as fenfluramine, dexfenfluramine,phentermine, sibutramine, orlistat, neuropeptide Y5 receptorantagonists, melanocortin 4 receptor agonists, cannabanoid CB-1 receptorantagonists, such as rimonabant, and β₃ adrenergic receptor agonists;

(m) ileal bile acid transporter inhibitors;

(n) antihypertensives including those acting on the angiotensin or reninsystems, such as angiotensin converting enzyme inhibitors, angiotensinII receptor antagonists or renin inhibitors, such as captopril,cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril,zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan,tasosartan, telmisartan, and valsartan; and

(o) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, andcyclo-oxygenase 2 selective inhibitors.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds having Formula I with two or more active compounds selectedfrom biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPARagonists, PTP-1B inhibitors, other DP-IV inhibitors, and anti-obesitycompounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.(For purposes of this application, topical application shall includemouth washes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require inhibition of dipeptidyl peptidase-IVenzyme activity an appropriate dosage level will generally be about 0.01to 500 mg per kg patient body weight per day which can be administeredin single or multiple doses. Preferably, the dosage level will be about0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kgper day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg perday. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, preferably once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of diabetes mellitus and/or hyperglycemia or hypertriglyceridemiaor other diseases for which compounds of the present invention areindicated, generally satisfactory results are obtained when thecompounds of the present invention are administered at a daily dosage offrom about 0.1 milligram to about 100 milligram per kilogram of animalbody weight, preferably given as a single daily dose or in divided dosestwo to six times a day, or in sustained release form. For most largemammals, the total daily dosage is from about 1.0 milligrams to about1000 milligrams, preferably from about 1 milligrams to about 50milligrams. In the case of a 70 kg adult human, the total daily dosewill generally be from about 7 milligrams to about 350 milligrams. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein.

The compounds of the present invention can be prepared from beta aminoacid intermediates such as those of formula II and substitutedheterocyclic intermediates such as those of formula III, using standardpeptide coupling conditions followed by deprotection. The preparation ofthese intermediates is described in the following schemes,

where Ar, R¹, R², R⁵, R⁶ and R⁹ are as defined above and P is a suitablenitrogen protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl, or 9-fluorenylmethoxycarbonyl (Fmoc).

Compounds of formula II are commercially available, known in theliterature or may be conveniently prepared by a variety of methodsfamiliar to those skilled in the art. One common route is illustrated inScheme 1. Acid 1, which may be commercially available or readilyprepared from the corresponding amino acid by protection using, forexample, di-tert-butyl dicarbonate (for P=Boc), carbobenzyloxy chloride(for P=Cbz), or N-(9-fluorenylmethoxycarbonyloxy)succinimide (forP=Fmoc), is treated with isobutyl chloroformate and a base such astriethylamine or diisopropylethylamine, followed by diazomethane. Theresultant diazoketone is then treated with silver benzoate in a solventsuch as methanol or aqueous dioxane and may be subjected to sonicationfollowing the procedure of Sewald et al., Synthesis, 837 (1997) in orderto provide the beta amino acid II. As will be understood by thoseskilled in the art, for the preparation of enantiomerically pure betaamino acids II, enantiomerically pure alpha amino acids 1 may be used.Alternate routes to these compounds can be found in the followingreviews: E. Juaristi, Enantioselective Synthesis of β-Amino Acids, Ed.,Wiley-VCH, New York: 1997, Juaristi et al., Aldrichimica Acta, 27, 3(1994), Cole et al., Tetrahedron, 32, 9517 (1994).

Compounds III are commercially available, known in the literature or maybe conveniently prepared by a variety of methods familiar to thoseskilled in the art. One convenient method is shown in Scheme 2. N-Boc3-piperidinone 2 is enolized with a base such as LHMDS at lowtemperature, e.g., −78° C., and the resultant enolate mixture is trappedby treatment with silyl chloride to give a mixture of silyl ethers 3aand 3b. Treatment with methyllithium followed by an acid anydride oracid chloride provides the beta-diketones 4a and 4b. The mixture may beseparated, or conveniently, used directly in the next step. Treatmentwith amidine 5 in the presence of a base such as sodium ethoxideprovides the Boc protected tetrahydropyridopyrimidine 6, followingremoval of the undesired isomer, for example by chromatographicpurification. The protecting group may be removed by treatment with TFAin dichloromethane to give the desired product III.

3-Oxopiperidine 1 and amidine 5 are commercially available, known in theliterature or may be conveniently prepared by a variety of methodsfamiliar to those skilled in the art. One convenient method forpreparation of amidine 5 is shown in Scheme 3. Nitrile 7, which itselfis commercially available, known in the literature, or convenientlyprepared by a variety of methods familiar to those skilled in the art,is treated with hydrogen chloride, conveniently as a solution indioxane, in ethanol to give imidate 8. Treatment with an ethanolicammonia solution provides amidine 5.

Compounds IIIa wherein R² is H may be conveniently prepared as shown inScheme 4. 3-Hydroxypiperidine 9 is protected, for example, as itsN-trityl derivative by treatment with trityl chloride and a base such astriethylamine to provide 10. Oxidation, conveniently using Swernconditions, gives 3-piperidinone 11. Treatment with1,1-dimethoxy-N,N-dimethylmethanamine in DMF at elevated temperaturegives enamine 12, which is condensed with amidine 5 in the presence of abase such as sodium ethoxide in ethanol to provide pyrimidine 13.Deprotection, in the case of trityl, with an acid such as hydrogenchloride gives tetrahydropyridopyrimidine IIIa.

The preparation of intermediate IIIb wherein R² is OH is illustrated inScheme 5. Ketoester 14 is treated with amidine 5 in the presence of abase such as sodium ethoxide in ethanol to providetetrahydropyridopyridimine 15. Deprotection of the nitrogen usingcatalytic hydrogenation, for example by treatment with hydrogen in thepresence of palladium on carbon, provides IIIb.

Intermediate 14 from Scheme 5 is commercially available, known in theliterature or may be conveniently prepared by a variety of methodsfamiliar to those skilled in the art. One convenient method forpreparation of 14 wherein R⁵ is not H is illustrated in Scheme 6.Intermediate 14a (R⁵=H) is treated with excess base, for example lithiumdiisopropylamide at a low temperature, conveniently −78° C., in asolvent such as THF with added HMPA to form the dianion. This isalkylated by treatment with an alkyl halide such as an alkyl bromide oralkyl iodide to provide intermediate 14.

The preparation of intermediate IIIc wherein R² is Cl is illustrated inScheme 7. Tetrahydropyridopyridimine 15, prepared as described in Scheme5, is treated with a chlorinating agent such as phenylphosphonicdichloride or phosphorus oxychloride, typically at elevated temperaturessuch as 100–200° C., to give chloropyrimidine 16. Deprotection of thenitrogen using 1-chloroethyl chloroformate provides IIIc.

An alternate method for the preparation of intermediate Ma wherein R² isH is illustrated in Scheme 8. Deprotection of intermediate 16, preparedas described in Scheme 7, using catalytic hydrogenation, for example bytreatment with hydrogen in the presence of palladium on carbon, providesIIIa.

Intermediate IIId wherein R² is alkoxy (OR⁴) may be prepared asillustrated in Scheme 9. Chloropyrimidine 16 is treated with alkoxideanion 17, for example sodium methoxide (R⁴=Me) or sodium ethoxide(R⁴=Et), to provide ether 18. Deprotection either using catalytichydrogenation or 1-chloroethyl chloroformate gives the desiredtetrahydropyridopyrimidine IIId.

Intermediate IIIe wherein R² is an amino group (NR⁷R⁸) may be preparedas illustrated in Scheme 10. Chloropyrimidine 16 is treated with ammoniaor a primary or secondary amine 19 to provide amine 20. Deprotectioneither using catalytic hydrogenation or 1-chloroethyl chloroformategives the desired tetrahydropyridopyrimidine IIIe.

Intermediates II and III are coupled under standard peptide couplingconditions, for example, using1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),1-hydroxybenzotriazole (HOBT), and a base, generallydiisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF)or dichloromethane for 3 to 48 hours at ambient temperature to provideintermediate 21 as shown in Scheme 11. The protecting group is thenremoved with, for example, trifluoroacetic acid or methanolic hydrogenchloride in the case of Boc to give the desired amine I. The product ispurified from unwanted side products, if necessary, byrecrystallization, trituration, preparative thin layer chromatography,flash chromatography on silica gel, or HPLC. Compounds that are purifiedby HPLC may be isolated as the corresponding salt. Purification ofintermediates is achieved in the same manner.

In some cases the intermediate 21 from the coupling reaction describedin Scheme 11 may be further modified before removal of the protectinggroup, for example, by manipulation of substituents on Ar, R¹, R², R⁵,R⁶ or R⁹. These manipulations may include, but are not limited to,reduction, oxidation, alkylation, acylation, and hydrolysis reactionswhich are commonly known to those skilled in the art. One such exampleis illustrated in Scheme 12. Intermediate 21a (R¹=SEt) is oxidized withmeta-chloroperbenzoic acid to provide sulfone 21b. The sulfone may thenbe displaced with nucleophiles such as ammonia or primary or secondaryamine 19 to provide the aminopyrimidine derivatives 21c, which are thendeprotected as described in Scheme 11.

Another such example is illustrated in Scheme 13. Intermediate 21d(R²=Cl) is treated with a nucleophile such as ammonia or primary orsecondary amine 19 to provide the aminopyrimidine derivative 21e, whichis then deprotected as described in Scheme 11.

An additional example is provided in Scheme 14. Intermediate 21f(R³=benzyloxy) is treated with hydrogen in the presence of a catalystsuch as palladium hydroxide to provide the phenol 21g, which may then bedeprotected as described in Scheme 11.

In some cases the final product I from Scheme 11 may be furthermodified, for example, by manipulation of substituents on Ar, R¹, R²,R⁵, R⁶ or R⁹. These manipulations may include, but are not limited to,reduction, oxidation, alkylation, acylation, and hydrolysis reactionswhich are commonly known to those skilled in the art.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way.

(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoicacid Step A.(R,S)-N-(1,1-Dimethylethoxycarbonyl)-2,5-difluorophenylalanine

To a solution of 0.5 g (2.49 mmol) of 2,5-difluoro-DL-phenylalanine in 5mL of tert-butanol were added sequentially 1.5 mL of 2N aqueous sodiumhydroxide solution and 543 mg of di-tert-butyl dicarbonate. The reactionwas stirred at ambient temperature for 16 h and diluted with ethylacetate. The organic phase was washed sequentially with 1N hydrochloricacid and brine, dried over magnesium sulfate and concentrated in vacuo.The crude material was purified by flash chromatography (silica gel,97:2:1 dichloromethane:methanol:acetic acid) to afford 671 mg of thetitle compound. MS 302 (M+1).

Step B.(R,S)-3-[(1,1-Dimethylethoxycarbonyl)amino]-1-diazo-4-(2,5-difluorophenyl)butan-2-one

To a solution of 2.23 g (7.4 mmol) of(R,S)-N-(1,1-dimethylethoxycarbonyl)-2,5-difluorophenylalanine in 100 mLof diethyl ether at 0° C. were added sequentially 1.37 mL (8.1 mmol) oftriethylamine and 0.931 mL (7.5 mmol) of isobutyl chloroformate and thereaction was stirred at this temperature for 15 min. A cooled etherealsolution of diazomethane was then added until the yellow color persistedand stirring was continued for a further 16 h. The excess diazomethanewas quenched by dropwise addition of acetic acid, and the reaction wasdiluted with ethyl acetate and washed sequentially with 5% hydrochloricacid, saturated aqueous sodium bicarbonate solution and brine, driedover magnesium sulfate and concentrated in vacuo. Purification by flashchromatography (silica gel, 4:1 hexane:ethyl acetate) afforded 1.5 g ofdiazoketone. ¹H NMR (500 MHz, CDCl₃) δ 7.03–6.95 (m, 1H), 6.95–6.88 (m,2H), 5.43 (bs, 1H), 5.18 (bs, 1H), 4.45 (bs, 1H), 3.19–3.12 (m, 1H),2.97–2.80 (m, 1H), 1.38 (s, 9H).

Step C.(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoicacid

To a solution of 2.14 g (6.58 mmol) of(R,S)-3-[(1,1-dimethylethoxycarbonyl)-amino]-1-diazo-4-(2,5-difluorophenyl)butan-2-onedissolved in 100 mL of methanol at −30° C. were added sequentially 3.3mL (19 mmol) of diisopropylethylamine and 302 mg (1.32 mmol) of silverbenzoate. The reaction was stirred for 90 min before diluting with ethylacetate and washing sequentially with 2N hydrochloric acid, saturatedaqueous sodium bicarbonate, and brine. The organic phase was dried overmagnesium sulfate, concentrated in vacuo and the enantiomers wereseparated by preparative chiral HPLC (Chiralpak AD column, 5% ethanol inhexanes) to give 550 mg of the desired (R)-enantiomer, which elutedfirst. This material was dissolved in 50 mL of a mixture oftetrahydrofuran:methanol: 1N aqueous lithium hydroxide (3:1:1) andstirred at 50° C. for 4 h. The reaction was cooled, acidified with 5%dilute hydrochloric acid and extracted with ethyl acetate. The combinedorganic phases were washed with brine, dried over magnesium sulfate andconcentrated in vacuo to give 360 mg of the title compound as a whitefoamy solid. ¹H NMR (500 MHz, CDCl₃) δ 7.21 (m, 1H), 6.98 (m, 2H), 6.10(bs, 1H), 5.05 (m,1H), 4.21 (m, 1H), 2.98 (m, 2H), 2.60 (m, 2H), 1.38(s, 9H).

(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-butanoicacid Step A.(2R,5S)-2,5-Dihydro-3,6-dimethoxy-2-(2′-fluoro-4′-(trifluoromethyl)benzyl)-5-isopropylpyrazine

To a solution of 3.32 g (18 mmol) of commercially available(2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 100 mL oftetrahydrofuran at −70° C. was added 12 mL (19 mmol) of a 1.6M solutionof butyllithium in hexanes. After stirring at this temperature for 20min, 5 g (19.5 mmol) of 2-fluoro-4-trifluoromethylbenzyl bromide in 20mL of tetrahydrofuran was added and stirring was continued for 3 hbefore warming the reaction to ambient temperature. The reaction wasquenched with water, concentrated in vacuo, and extracted with ethylacetate. The combined organic phase was washed with brine, dried, andconcentrated in vacuo. Purification by flash chromatography (silica gel,0–5% ethyl acetate in hexanes) afforded 5.5 g of the title compound. ¹HNMR (500 MHz, CDCl₃) δ 7.33–7.25 (m, 3H), 4.35–4.31 (m, 1H), 3.75 (s,3H), 3.65 (s, 3H), 3.60 (t, 1H, J=3.4 Hz), 3.33 (dd, 1H, J=4.6, 13.5Hz), 3.03 (dd, 1H, J=7, 13.5 Hz), 2.25–2.15 (m, 1H), 1.0 (d, 3H, J=7Hz), 0.66 (d, 3H, J=7 Hz).

Step B.(R)-N-(1,1-Dimethylethoxycarbonyl)-2-fluoro-4-(trifluoromethyl)phenylalaninemethyl ester

To a solution of 5.5 g (15 mmol) of(2R,5S)-2,5-dihydro-3,6-dimethoxy-2-(2′-fluoro-4′-(trifluoromethyl)benzyl)-5-isopropylpyrazinein 50 mL of a mixture of acetonitrile:dichloromethane (10:1) was added80 mL of 1N aqueous trifluoroacetic acid. The reaction was stirred for 6h and the organic solvents were removed in vacuo. Sodium carbonate wasadded until the solution was basic (>pH 8), and then the reaction wasdiluted with 100 mL of tetrahydrofuran and 10 g (46 mmol) ofdi-tert-butyl dicarbonate was added. The resulting slurry was stirredfor 16 h, concentrated in vacuo, and extracted with ethyl acetate. Thecombined organic phase was washed with brine, dried, and concentrated invacuo. Purification by flash chromatography (silica gel, 20% ethylacetate in hexanes) afforded 5.1 g of the title compound. ¹H NMR (500MHz, CDCl₃) δ 7.38–7.28 (m, 3H), 5.10 (bd, 1H), 4.65–3.98 (m, 1H), 3.76(s, 3H), 3.32–3.25 (m, 1H), 3.13–3.05 (m, 1H), 1.40 (s, 9H).

Step C.(R)-N-(1,1-Dimethylethoxycarbonyl)-2-fluoro-4-(trifluoromethyl)phenylalanine

A solution of 5.1 g (14 mmol) of(R,S)-N-(1,1-dimethylethoxycarbonyl)-2-fluoro-4-(trifluoromethyl)phenylalaninemethyl ester in 350 mL of a mixture of tetrahydrofuran:methanol:1Nlithium hydroxide (3:1:1) was stirred at 50° C. for 4 h. The reactionwas cooled, acidified with 5% dilute hydrochloric acid and extractedwith ethyl acetate. The combined organic phases were washed with brine,dried over magnesium sulfate and concentrated in vacuo to give 4.8 g ofthe title compound. ¹H NMR (500 MHz, CD₃OD) δ 7.45–7.38 (m, 3H),4.44–4.40 (m, 1H), 3.38–3.33 (m, 1H), 2.98 (dd, 1H, J=9.6, 13.5 Hz),1.44 (s, 9H).

Step D.(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-[2-fluoro-4-(trifluoromethyl)phenyl]butanoicacid

To a solution of 3.4 g (9.7 mmol) of the product from Step C in 60 mL oftetrahydrofuran at 0° C. were added sequentially 2.3 mL (13 mmol) ofdiisopropylethylamine and 1.7 mL (13 mmol) of isobutyl chloroformate andthe reaction was stirred at this temperature for 30 min. A cooledethereal solution of diazomethane was then added until the yellow colorpersisted and stirring was continued for a further 16 h. The excessdiazomethane was quenched by dropwise addition of acetic acid, and thereaction was diluted with ethyl acetate and washed sequentially with 5%hydrochloric acid, saturated aqueous sodium bicarbonate solution andbrine, dried over magnesium sulfate and concentrated in vacuo.Purification by flash chromatography (silica gel, 9:1 hexane:ethylacetate) afforded 0.5 g of diazoketone. To a solution of 0.5 g (1.33mmol) of the diazoketone dissolved in 100 mL of methanol at 0° C. wereadded sequentially 0.7 mL (4 mmol) of diisopropylethylamine and 32 mg(0.13 mmol) of silver benzoate. The reaction was stirred for 2 h beforediluting with ethyl acetate and washing sequentially with 2Nhydrochloric acid, saturated aqueous sodium bicarbonate, and brine. Theorganic phase was dried over magnesium sulfate, concentrated in vacuoand dissolved in 50 mL of a mixture of tetrahydrofuran:methanol:1Naqueous lithium hydroxide (3:1:1) and stirred at 50° C. for 3 h. Thereaction was cooled, acidified with 5% dilute hydrochloric acid andextracted with ethyl acetate. The combined organic phases were washedwith brine, dried over magnesium sulfate and concentrated in vacuo togive 410 mg of the title compound as a white foamy solid. ¹H NMR (500MHz, CD₃OD) δ 7.47–7.33 (m, 3H), 4.88 (bs, 1H), 4.26–3.98 (m, 1H),3.06–3.01 (m, 1H), 2.83–2.77 (m, 1H), 2.58–2.50 (m, 2H), 1.29 (s, 9H).

(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoicacid Step A.(2S,5R)-2,5-Dihydro-3,6-dimethoxy-2-isopropyl-5-(2′,4′,5′trifluorobenzyl)pyrazine

The title compound (3.81 g) was prepared from 3.42 g (18.5 mmol) of(2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine and 5 g (22.3 mmol)of 2,4,5-trifluorobenzyl bromide using the procedure described forIntermediate 2, Step A. ¹H NMR (500 MHz, CDCl₃) δ 7.01 (m, 1H), 6.85 (m,1H), 4.22 (m, 1H), 3.78 (m, 3H), 3.64 (m, 3H), 3.61 (m, 1H), 3.20 (m,1H), 2.98 (m, 1H), 2.20 (m, 1H), 0.99 (d, 3H, J=8 Hz), 0.62 (d, 3H, J=8Hz).

Step B. (R)-N-(1,1-Dimethylethoxycarbonyl)-2,4,5-trifluorophenylalaninemethyl ester

To a solution of 3.81 g (11.6 mmol) of(2S,5R)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(2′,4′,5′trifluoro-benzyl)pyrazinein 20 mL of acetonitrile was added 20 mL of 2N hydrochloric acid. Thereaction was stirred for 72 h and concentrated in vacuo. The residue wasdissolved in 30 mL of dichloromethane and 10 mL (72 mmol) oftriethylamine and 9.68 g (44.8 mmol) of di-tert-butyldicarbonate wereadded. The reaction was stirred for 16 h, diluted with ethyl acetate andwashed sequentially with 1N hydrochloric acid and brine. The organicphase was dried over sodium sulfate, concentrated in vacuo and purifiedby flash chromatography (silica gel, 9:1 hexanes:ethyl acetate) toafford 2.41 g of the title compound. ¹H NMR (500 MHz, CDCl₃) δ 6.99 (m,1H), 6.94 (m, 1H), 5.08 (m, 1H), 4.58 (m, 1H), 3.78 (m, 3H), 3.19 (m,1H), 3.01 (m, 1H), 1.41 (s, 9H).

Step C. (R)-N-(1,1-Dimethylethoxycarbonyl)-2,4,5-trifluorophenylalanine

The title compound (2.01 g) was prepared from 2.41 g (7.5 mol) of(R)-N-(1,1-dimethylethoxycarbonyl)-2,4,5-trifluorophenylalanine methylester using the procedure described for Intermediate 2, Step C. LC-MS220.9 (M+1-BOC).

Step D.(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoicacid

To a solution of 0.37 g (1.16 mmol) of(R)-N-(1,1-dimethylethoxycarbonyl)-2,4,5-trifluorophenylalanine in 10 mLof diethyl ether at −20° C. were added sequentially 0.193 mL (1.3 mmol)of triethylamine and 0.18 mL (1.3 mmol) of isobutyl chloroformate, andthe reaction was stirred at this temperature for 15 min. A cooledethereal solution of diazomethane was then added until the yellow colorpersisted and stirring was continued for a further 1 h. The excessdiazomethane was quenched by dropwise addition of acetic acid, and thereaction was diluted with ethyl acetate and washed sequentially withsaturated aqueous sodium bicarbonate solution and brine, dried overmagnesium sulfate and concentrated in vacuo. Purification by flashchromatography (silica gel, 3:1 hexane:ethyl acetate) afforded 0.36 g ofdiazoketone. To a solution of 0.35 g (1.15 mmol) of the diazoketonedissolved in 12 mL of 1,4-dioxane: water (5:1) was added 26 mg (0.113mmol) of silver benzoate. The resultant solution was sonicated for 2 hbefore diluting with ethyl acetate and washing sequentially with 1Nhydrochloric acid and brine, drying over magnesium sulfate andconcentrating in vacuo. Purification by flash chromatography (silicagel, 97:2:1 dichloromethane:methanol:acetic acid) afforded 401 mg of thetitle compound. ¹H NMR (500 MHz, CDCl₃) δ 7.06 (m, 1H), 6.95 (m, 1H),5.06 (bs, 1H), 4.18 (m, 1H), 2.98 (m, 2H), 2.61 (m, 21), 1.39 (s, 9H).

(3R)-4-(2-Bromo-4,5-difluorophenyl)-3-[(1,1-dimethylethoxycarbonyl)amino]butanoicacid

To a solution of 2.4 g (10 mmol) of 2-bromo-4,5-difluorobenzoic acid(prepared according to the procedure of Braish et al., SyntheticCommun., pg 3067–3074, 1992) in 75 mL of tetrahydrofuran was added 2.43g (15 mmol) of carbonyldiimidazole. The solution was heated under refluxfor 3.5 h, cooled to ambient temperature and 0.38 g (10 mmol) of sodiumborohydride in 15 mL of water was added. The reaction was stirred for 10min and partitioned between ethyl acetate and 10% aqueous sodiumbicarbonate solution. The organic layer was washed twice with warmwater, brine, dried over magnesium sulfate, and concentrated in vacuo.Purification by flash chromatography (silica gel, 4:1 hexane:ethylacetate) afforded 1.9 g of 2-bromo-4,5-difluorobenzyl alcohol. To asolution of 1.9 g (8.4 mmol) of 2-bromo-4,5-difluorobenzyl alcohol in 30mL of dichloromethane at 0° C. was added 3.4 g (10 mmol) of carbontetrabromide and 2.7 g (10 mmol) of triphenylphosphine. The reaction wasstirred for 2 h at this temperature, the solvent was removed in vacuoand the residue stirred with 100 mL of diethyl ether. The solution wasfiltered, concentrated in vacuo, and purified by flash chromatography(silica gel, 20:1 hexane:ethyl acetate) to afford 2.9 g of2-bromo-4,5-difluorobenzyl bromide contaminated with carbon tetrabromidewhich was used without further purification. Using the proceduresoutlined for the preparation of Intermediates 2 and 3, the benzylbromide derivative was converted to the title compound: LC-MS 394 and396 (M+1).

Essentially following the procedures outlined for the preparation ofIntermediates 1–4, the Intermediates in Table 1 were prepared.

TABLE 1

Intermediate R³ Selected ¹H NMR data (CD₃OD) 5 2-F, 4-Cl, 5-F 7.11 (dd,1H, J = 8.9, 6.4 Hz), 7.03 (dd, 1 H, J = 9.0, 6.6) 6 2-F, 5-Cl 7.27 (dd,1H, J = 6.4, 2.5 Hz), 7.21 (m, 1 H), 7.03 (t, 1H, J = 9.2 Hz 7 2-Me,5-Cl 7.16 (d, 1H, J = 1.8 Hz), 7.11–7.07 (m, 2 H), 2.34 (s, 3H) 8 2-Cl,5-Cl 7.34 (d, 1H, J = 9.0), 7.33 (d, 1H, J = 2.1 Hz), 7.21 (dd, 1H, J =8.5, 2.5 Hz) 9 2-F, 3-Cl, 6-F 7.35 (td, 1H, J = 8.5, 5.8 Hz), 6.95 (t, 1H, J = 8.5 Hz) 10 3-Cl, 4-F 7.33 (d, 1H, J = 6.9 Hz), 7.19–7.11 (m, 2 H)11 2-F, 3-F, 6-F 7.18–7.12 (m, 1H), 6.91 (m, 1H) 12 2-F, 4-F, 6-F 6.81(t, 2H, J = 8.4 Hz) 13 2-OCH₂Ph, 5-F 7.49 (d, 2H, J = 7.6 Hz), 7.38 (t,2H, J = 7.3 Hz), 7.30 (t, 1H, J = 7.3 Hz), 6.96– 6.89 (m, 3H), 5.11 (d,1H, J = 11.7 Hz), 5.08 (d, 1H, J = 11.9 Hz)

EXAMPLE 1

7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-olStep A.7-(Phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

To a solution of sodium ethoxide, prepared from 3.2 g (133 mmol) ofsodium metal and 200 mL of absolute ethanol, at ambient temperature wasadded 8.3 g (74 mmol) of trifluoroacetamidine followed by 17.8 g (60mmol) of ethyl 1-benzyl-3-oxopiperidinecarboxylate hydrochloride inportions over 15 min. The reaction mixture was stirred at ambienttemperature for 1 h, then heated at reflux for 30 h. The mixture wasconcentrated in vacuo. The resultant red foam was partitioned between300 mL of 1 N aqueous sodium hydroxide solution and 300 mL of ether. Theaqueous layer was washed with 300 mL of ether and the combined etherphases were extracted with 50 mL of 1 N aqueous sodium hydroxidesolution. The combined aqueous phases were cooled in an ice-water bathand neutralized to pH 7 with concentration hydrochloric acid. The solidswere collected, washed with water, and dried in vacuo to give 13.99(75%) of beige solid, which was used as is. An analytical sample wasprepared by recrystallization of 200 mg from isopropanol to give 157 mgof a white powder. LC-MS 310.0 (M+1).

Step B.2-(Trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol,acetic acid salt

A mixture of 160 mg (0.52 mmol) of benzylamine from Step A, 5 mL ofacetic acid and ˜50 mg of 5% Pd/C was shaken on a Parr apparatus under40 psi of hydrogen for 5 h. The reaction was judged to be 80–90%complete by LC-MS analysis. An additional ˜20 mg of 5% Pd/C was addedand the reaction was shaken under 40 psi of hydrogen for 3 h. Thereaction mixture was filtered and concentrated. The resultant solid wastriturated with ether twice and dried in vacuo to give 118 mg (81%) ofthe title compound. LC-MS 220.0 (M+1).

Step C.7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

A suspension of 30 mg (0.10 mmol) of(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2,5-difluorophenyl)butanoicacid, 34 mg (0.12 mmol) of amine from Step B, 25 mg (0.12 mmol) of ethyldimethylaminopropylcarbodiimide (EDC), and 18 mg (0.12 mmol) ofhydroxybenzotriazole (HOBt) in 1.0 mL of dichloromethane was treatedwith 0.050 mL of diisopropylethylamine. The reaction mixture wassonicated for 5 min, then shaken for 3 days at ambient temperature. Themixture was diluted with 1 mL of dichloromethane, treated with 2 mL oftrifluoroacetic acid (TFA), and concentrated in vacuo. Purification byHPLC (YMC C18 Pro column, gradient elution, 10–90% MeCN:H₂O containing0.1% TFA) gave 40 mg of a viscous gum which was converted to free baseon a 1-g SCX column to provide 25 mg of a white solid. The solid wastriturated with ether, collected and dried under vacuo to give 21.2 mgof the title compound as a white powder. LC-MS 417.1 (M+1).

EXAMPLE 2

7-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,dihydrochloride Step A.4-Chloro-7-(phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A mixture of 29.6-g (95.7 mmol) of7-(phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol(prepared essentially as described in Example 1, Step A) and 53 mL ofphenylphosphonic dichloride in a 250-mL round bottom flask was heated at150° C. After 2 h, the reaction was judged to be complete by TLCanalysis. The mixture was cooled to ambient temperature and poured onto400 g of ice, transferring with ˜500 mL of ethyl acetate. The aqueouslayer was neutralized with solid sodium bicarbonate and the layersseparated. The aqueous layer was extracted with two portions of ethylacetate. The combined organics were washed sequentially with saturatedaqueous sodium bicarbonate solution and brine, dried over sodium sulfateand concentrated to give a brown solid. The solid was boiled in 2 L ofhexane with charcoal, filtered, and concentrated in vacuo to give 23.9 g(76%) of the title compound as a yellow solid. LC-MS 328.3 (M+1).

Step B. 2-(Trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,hydrochloride

A flask containing a solution of 23.4 g (71.41 mmol) of amine from StepA in 285 mL of ethyl acetate and 530 mL of methanol was purged withnitrogen, and 2 g of 10% Pd/C was added. The mixture was stirred under 1atm of hydrogen until the reaction was judged complete by TLC analysis(˜7.5 h total). The mixture was filtered through Celite, and the Celitewashed with methanol. The organics were concentrated in vacuo and theresultant pale yellow oil was triturated with 400 mL of ether. Crystalsformed and an additional 400 mL of ether was added. The mixture wasstirred overnight. The resultant solid was collected by filtration anddried in vacuo to give 16.3 g of off-white crystals that contained animpurity by TLC analysis. The crystals were dissolved in a minimumamount of methanol. Ether was added to turbidity and the mixture waswarmed on a steam bath. Crystals formed and the mixture was allowed tocool to ambient temperature and aged for 30 min. It was then filtered.The collected solid was dried in vacuo to give 14.8 g of the titlecompound as a white crystalline solid. LC-MS 203.8 (M+1).

Step C.7-[(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A 1-L round bottom flask was charged with 15.5 g (46.5 mmol) of(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2,4,5-trifluorophenyl)butanoicacid and 160 mL of acetonitrile. To the resultant suspension was added14.5 g (60.5 mmol) of amine hydrochloride from Step B. The mixture wascooled to 5° C. and 12 g (62.8 mmol) of EDC and 6.9 mL (62.8 mmol) ofN-methylmorpholine were added. After 2 h, the reaction was judged to becomplete by LC-MS analysis. The mixture was partitioned between 100 mLof water and 160 mL of ethyl acetate. The organic phase was washedsequentially with 100 mL of saturated aqueous sodium bicarbonatesolution and 100 mL of brine, dried over sodium sulfate, andconcentrated in vacuo. Purification by Biotage flash chromatography(silica gel, 30–60% ethyl acetate/hexane) gave 20.3 g of the titlecompound as a white foam. LC-MS 419.4 (M+1-BOC).

Step D.7-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,dihydrochloride

A solution of 26.5 g (51.1 mmol) of7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinein 130 mL of methanol was cooled to 0° C. and 130 mL of 9 N aqueoushydrochloric acid was added. The mixture was allowed to warm to ambienttemperature, stirred overnight, and the methanol removed in vacuo. Theaqueous residue was neutralized by the addition of sodium hydroxide andextracted with ethyl acetate. The organic phase was washed sequentiallywith 1 N aqueous sodium hydroxide solution and brine, dried over sodiumsulfate and concentrated in vacuo. Purification by Biotage flashchromatography (silica gel, 5–10% methanol/dichloromethane) gave 17.5 gof a brown oil. To a mixture of 16.5 g of this oil in 50 mL of water wasadded 3.45 mL of concentrated hydrochloric acid. The mixture was stirredvigorously for ˜2 h until a solution was formed. The resultant solutionwas lyophilized overnight, dissolved in ˜50 mL of water, and lyophilizedagain to provide 17.8 g of the title compound as a white solid. LC-MS419.3 (M+1).

EXAMPLE 3

7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-4-methoxy-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,dihydrochloride Step A.4-Methoxy-7-(phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

4-Chloro-7-(phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(98 mg, 0.30 mmol) and 1.5 mL of 0.5 M sodium methoxide in methanol waswarmed to 60° C. overnight. The mixture was concentrated under nitrogenand partitioned between ether and water. The ether layer was washed withbrine, dried and concentrated to give 94 mg of the title compound as ayellow oil. LC-MS 324.0 (M+1).

Step B.4-Methoxy-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,hydrochloride

A solution of 94 mg (0.30 mmol) of the anine from Step A in 1.5 mL ofdichloromethane was treated with 0.041 mL (0.375 mmol) of 1-chloroethylchloroformate. The solution was warmed to 45° C. for 18 h, cooled toroom temperature, and concentrated under nitrogen. A 1.5-mL portion ofmethanol was added and the mixture was warmed to 40° C. for 2 h, cooled,and concentrated under nitrogen and then in vacuo. Trituration withether followed by drying of the resultant off-white solid in vacuo gave73 mg (90%) of the title compound. LC-MS 234.2 (M+1).

Step C.7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-4-methoxy-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,dihydrochloride

A mixture of 43 mg (0.13 mmol) of(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2,5-difluorophenyl)butanoicacid, 35 mg (0.13 mmol) of amine from Step B, 25 mg (0.13 mmol) of EDC,18 mg (0.13 mmol) of HOBt, and 0.052 mL of diisopropylethylamine in 1.0mL of dichloromethane was stirred overnight at ambient temperature. Themixture was purified directly by preparative TLC (1 mm silica gel, 35%ethyl acetate/hexane) to give 60 mg of the Boc intermediate. Theintermediate was treated with 3 mL of dichloromethane and 2 mL of TFA atroom temperature for 1 h. The reaction mixture was concentrated undernitrogen. The resultant TFA salt was converted to the free base on a 1-gSCX column, eluting the product with 1 M ammonia in methanol. Themethanol and excess ammonia were removed in vacuo, and the residue wastreated with 1 M hydrogen chloride in ethyl acetate and ether was added.Trituration of the product from ether-hexane gave 46.7 mg of the titlecompound as an off-white powder. LC-MS 431.0 (M+1).

EXAMPLE 4

7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-4-amino-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,dihydrochloride Step A.4-Chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,hydrochloride

4-Chloro-7-(phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(262 mg, 0.80 mmol) was debenzylated following a procedure similar tothat described in Example 3, Step B. Trituration with ether gave 208 mg(95%) of the title compound as an off-white solid. LC-MS 238.1 (M+1).

Step B.7-[(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoyl]-4-chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A mixture of 60 mg (0.20 mmol) of(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2,5-difluorophenyl)butanoicacid and 0.033 mL (0.30 mmol) of N-methylmorpholine in 0.6 mL of THF wascooled to −15° C. and 0.031 mL of isobutyl chloroformate was added.After 10 min, 1.0 mL of ether was added. The mixture was transferred toa syringe and filtered through a syringe filter into a mixture of 35 mg(0.20 mmol) of amine hydrochloride from Step A and 0.033 mL (0.30 mmol)of N-methylmorpholine in 0.5 mL of THF at 0° C. The reaction mixture waswarmed to ambient temperature. After 30 min, the reaction was judged tobe complete by TLC. The mixture was filtered using a syringe filter,washing with ether, and concentrated under nitrogen. The solid waspartitioned between ethyl acetate and water. The organics were washedwith brine, dried over magnesium sulfate and concentrated to give ayellow oil. Purification by flash chromatography (5 g silica gelcartridge, 10 to 35% ethyl acetate/hexane step gradient) gave 62 mg(58%) of the title compound as a white solid.

Step C.7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-4-amino-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinedihydrochloride

A mixture of 62 mg (0.116 mmol) of chloro derivative from Step B and 2mL of 0.5 M ammonia in THF was heated in a sealed tube at 60° C. for 20h. The reaction mixture cooled, and concentrated under nitrogen to give70 mg of Boc intermediate which was deprotected and converted to thehydrochloride salt following a procedure similar to that described forExample 3, Step C. Trituration with ether gave 19.9 mg of the titlecompound. LC-MS 416.1 (M+1).

EXAMPLE 5

7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-2-[6-(trifluoromethyl)pyrin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,dihydrochloride Step A.7-Benzyl-2-[6-(trifluoromethyl)pyridin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

A mixture of 258 mg (11.2 mmol) of sodium in 10 mL of absolute ethanolwas stirred at ambient temperature for 1 h. To the resultant sodiumethoxide solution was added 893 mg (3.0 mmol) of ethyl1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride in portionsfollowed by 840 mg (3.72 mmol) of 6-(trifluoromethyl)pyridine-3-amidinehydrochloride. The reaction mixture was heated at reflux for 18 h, thenconcentrated in vacuo. To the residue was added ˜30 mL of 1N aqueoussodium hydroxide solution and 15 mL of water to give an insoluble solidand a yellow solution. The solid was filtered off and washed with waterto provide 496 mg of the title compound. The aqueous filtrate wasacidified to ˜pH 5 with concentrated hydrochloric acid and the solidprecipitate was collected to give an additional 334 mg of the titlecompound as a bright yellow powder (72% total yield). LC-MS 387.2 (M+1).

Step B.7-Benzyl-4-chloro-2-[6-(trifluoromethyl)pyridin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A mixture of 232 mg (0.6 mmol) of7-benzyl-2-[6-(trifluoromethyl)pyridin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-olfrom Step A and 1.0 mL of phosphorous oxychloride in a 25-mL roundbottom flask was treated with 90 mg (0.095 mL, 0.6 mmol) ofN,N-diethylaniline. The mixture was warmed to 110° C. After 4 h, it wascooled to ambient temperature and concentrated in vacuo. Water (15–20mL) was added. The mixture was neutralized by the addition of solidsodium bicarbonate and extracted with 2 portions of ethyl acetate. Thecombined organic phases were washed with brine, dried, and concentrated.Purification by flash chromatography (silica gel, 0 to 20% ethylacetate/hexane step gradient) gave 220 mg of a light yellow oil. LC-MS405.2 (M+1).

Step C.2-[6-(Trifluoromethyl)pyridin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,hydrochloride

A mixture of 220 mg of7-benzyl-4-chloro-2-[6-(trifluoromethyl)pyridin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidineand 40–50 mg of 10% palladium on carbon in 8 mL of methanol and 5 mL ofethyl acetate was stirred under 1 atm of hydrogen for 3 h. The mixturewas filtered and concentrated to give a yellow solid. Trituration withether gave 120 mg of the title compound as an off-white powder. LC-MS281.1 (M+1).

Step D.7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-2-[6-(trifluoromethyl)pyridin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,dihydrochloride

A mixture of 60 mg (0.20 mmol) of(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoicacid and 0.033 mL (0.30 mmol) of N-methylmorpholine in 0.6 mL of THF wascooled to −15° C. and 0.031 mL (0.24 mmol) of isobutyl chloroformate wasadded. After 10 min, 1.0 mL of dry ether was added. After 2 min, themixture was transferred to a syringe and filtered through a syringefilter into a mixture of 63 mg (0.20 mmol) of2-[6-(trifluoromethyl)pyridin-3-yl]-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinehydrochloride and 0.033 mL (0.30 mmol) of N-methylmorpholine in 0.8 mLof THF at 0° C. The reaction mixture was warmed to ambient temperature.After 30 min, the mixture was concentrated in vacuo. After attemptedtrituration proved problematic, purification by flash chromatography (5g silica gel cartridge, 15 to 50% ethyl acetate/hexane step gradient)gave 68 mg of the Boc protected intermediate. This was treated with TFAin methanol at ambient temperature for 1 h and concentrated. The productwas converted to free base on a 1 g SCX column, eluting the product with1 M ammonia in methanol. The hydrochloride salt was formed by treatmentwith 1 M hydrogen chloride in ethyl acetate. Trituration with ether gave47 mg of the title compound as a light yellow powder. LC-MS 478.2 (M+H).

EXAMPLE 6

7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-N-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine,bis(trifluoroacetic acid) salt Step A.3-Hydroxy-1-(triphenylmethyl)piperidine

To a stirred suspension of 1.37 g (10.0 mmol) of 3-hydroxypiperidinehydrochloride and 2.53 g (3.5 mL) of triethylamine in 30 mL ofdichloromethane at 0° C. was added dropwise 2.93 g (10.5 mmol) of tritylchloride. The mixture was stirred at ambient temperature overnight,diluted with 100 mL of dichloromethane, washed sequentially with water,5% aqueous citric acid solution, saturated sodium bicarbonate solution,and brine, dried over sodium sulfate, and concentrated to give 3.85 g ofthe title compound as a white foam.

Step B. 1-Tritylpiperidin-3-one

To a solution of 1.7 mL (24 mmol) of DMSO in 30 mL of dichloromethane at−50° C. was added dropwise 5.5 mL (11.0 mmol) of 2.0 M oxalyl chloridesolution in dichloromethane. After 10 min, a solution of 3.85 g (10.0mmol) of 3-hydroxy-1-(triphenylmethyl)piperidine from Step A in 15 mL ofdichloromethane was added dropwise. After 15 min, 7.0 mL (50 mmol) oftriethylamine was added dropwise. The reaction mixture was allowed towarm to ambient temperature over 0.5 h. The mixture was diluted withdichloromethane, washed sequentially with water, 5% aqueous citric acidsolution, saturated sodium bicarbonate solution, and brine, dried oversodium sulfate and concentrated. Purification by flash chromatography(silica gel, 6% ethyl acetate/hexane) gave 1.95 g (57%) of the titlecompound as a white crystalline solid.

Step C. 4-[(Dimethylamino)methylene]-1-tritylpiperidin-3-one

A mixture of 1.94 g (5.68 mmol) of piperidinone from Step B in 10 mL ofDMF was treated with 0.677 g (0.755 mL) of1,1-dimethoxy-N,N-dimethylmethylamine. The colorless suspension waswarmed to 80° C. under nitrogen. After 18 h, the mixture was cooled toambient temperature and concentrated in vacuo. The dark red residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over magnesium sulfate and concentrated to give2.25 g of a pale yellow-orange foam. Crystallization of a 2.03-g portionfrom ether (2 crops) gave a total of 1.17 g (52%) of the title compound.

Step D. 2-(Ethylthio)-7-trityl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A 148-mg (0.80 mmol) portion of ethyl imidothiocarbamate hydrobromide in1.5 mL of absolute ethanol was treated with 0.30 mL of 2.68 M sodiumethoxide solution in ethanol. After 10 min, 158 mg (0.40 mmol) of ketonefrom Step C in 0.5 mL of ethanol was added. The reaction flask wassealed under nitrogen and warmed at 80° C. overnight, then concentratedunder nitrogen and in vacuo. The residue was partitioned between ethylacetate and water. The organic later was concentrated to give 200 mg ofa red-orange gum. Purification by preparative TLC (silica gel, 15% ethylacetate/hexane) gave 81 mg (41%) of the title compound as an off-whitefoam.

Step E. 2-(Ethylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,hydrochloride

A suspension of 81 mg (0.185 mmol) of trityl compound from Step D in 0.5mL of methanol was treated with 4 N hydrogen chloride solution indioxane. The reaction mixture was stirred at ambient temperature for 2h, then concentrated under nitrogen and then in vacuo. Trituration withether gave 47 mg (˜100%) of the title compound as a pale yellow solid.

Step F.7-[(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoyl]-2-(ethylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A mixture of 47 mg (0.19 mmol) of2-(ethylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride,59 mg (0.19 mmol) of(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoicacid, 37 mg (0.19 mmol) of EDC, 26 mg (0.19 mmol) of HOBt, and 0.15 mL(0.57 mmol) of diisopropylethylamine in 1.5 mL of dichloromethane wasstirred at ambient temperature overnight. The mixture was subjecteddirectly to purification by flash chromatography (5 g silica gelcartridge, 20-to-50% ethyl acetate/hexane step gradient) to give 85 mg(91%) of the title compound as a white solid.

Step G.7-[(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoyl]-2-(ethylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyridine

Thioether from Step F (85 mg, 0.173 mmol) in 1.5 mL of THF was cooled to0° C. and 75 mg (0.367 mmol) of m-chloroperbenzoic acid was added in oneportion. After 10 min, the reaction mixture was warmed to ambienttemperature, stirred for 1.5 h, and concentrated under nitrogen. Theresidue was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate solution to give 105 mg of crude product.Purification by flash chromatography (2-g silica gel cartridge, 50% then100% ethyl acetate/hexane) gave 70 mg (77%) of the title compound as awhite foam.

Step H.7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-N-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine,bis(trifluoroacetic acid) salt

Sulfone (36 mg, 0.069 mmol) from Step G and 1.0 mL of 2.0 M methylaminesolution in THF were sealed under nitrogen and warmed at 65° C.overnight. The mixture was cooled, concentrated under nitrogen, andpurified by preparative TLC (silica gel, 5% methanol/dichloromethane) togive 24.2 mg (76%) of the Boc intermediate. Deprotection was achieved bytreatment with 3 mL of TFA in 5 mL of dichloromethane at ambienttemperature. Once the reaction was judged to be complete, the mixturewas concentrated. The residue was dissolved in ethyl acetate andconcentrated to remove excess TFA. Trituration with ether gave 24 mg ofthe title compound as a pale yellow powder. LC-MS 362.1 (M+1).

EXAMPLE 7

7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-2-(4-chlorophenyl)-4-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,trifluoroacetic acid salt Step A. tert-Butyl5-[(trimethylsilyl)oxy]-3,4-dihydropyridine-1(2H)-carboxylate andtert-Butyl 5-[(trimethylsilyl)oxy]-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of 115 mL of 1.0 M THF solution of lithiumhexamethyldisilyl amide in 290 mL of anhydrous THF in a dried 1-L roundbottom flask under nitrogen at −78° C. was added dropwise a solution of20 g (0.1004 mmol) of tert-butyl 3-oxopiperidine-1-carboxylate in 150 ofTHE via canula over a 1-h period. The reaction mixture was stirred at−78° C. for 50 min, then 18 mL (1.4 equiv) of trimethylsilyl choride wasadded in portions. The mixture was stirred 30 min, warmed to ambienttemperature and stirred an additional 30 min, then concentrated to asmall volume in vacuo at 25° C. It was partitioned between hexane and1:1 water:saturated aqueous sodium carbonate solution. The aqueous phasewas extracted with two portions of hexane. The combined organics werewashed with brine, dried over sodium sulfate, and concentrated at 25° C.in vacuo to give 31.87 g of the title compounds as a yellow oil.

Step B. tert-butyl 3-oxo-4-(trifluoroacetyl)piperidine-1-carboxylate andtert-butyl 3-oxo-2-(trifluoroacetyl)piperidine-1-carboxylate

To a dried 100-mL round bottom flask was added 11.5 mL of methyllithium(1.6 M solution in ether). The ether was removed in vacuo and the flaskcharged with 40 mL of dry THF. The mixture was cooled to −15° C. and asolution of 5.0 g (18.42 mmol) of enol ethers from Step A in 40 mL ofdry THF was added. The mixture was stirred at −15° C. for an additional40 min, cooled to −78° C., and transferred slowly via cannula over 30min to a solution of 2.6 mmol of trifluoroacetic anhydride in 100 mL ofdry THF. The mixture was stirred at −78° C. for an additional 1 h, thenquenched by the addition of 5 mL of saturated aqueous ammonium chloridesolution, warmed to room temperature, and concentrated in vacuo. Theresidue was partitioned between ethyl acetate and water. The organicswere concentrated to give 6.1 g of an orange oil. Purification by flashchromatography (silica gel, eluting sequentially with 20%, 40% and 60%ethyl acetate/hexane) gave 1.91 g of the title compound (5:1 isomericmixture) as an orange oil.

Step C. tert-butyl2-(4-chlorophenyl)-4-(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate

A solution of 144 mg (0.51 mmol) of 4-chlorobenzamidine in 0.5 mL ofabsolute ethanol was treated with 0.229 mL of sodium ethoxide solution(21 wt. % in ethanol) and stirred at ambient temperature for 10 min. Theresultant orange solution was treated with 100 mg (0.34 mmol) of themixture of diketones from Step B in a total of 0.8 mL of absoluteethanol. The reaction mixture was stirred at ambient temperature for 20min, then warmed to 80° C. overnight, cooled and concentrated. Theresidue was partitioned between ethyl acetate and water. The organicphase was washed with brine, dried over sodium sulfate, and concentratedto give 170 mg of an orange semisolid. Trituration with 5 mL of ethergave 150 mg of an orange, viscous oil. Purification by flashchromatography (silica gel, eluting sequentially with 0, 10, and 20%ethyl acetate/hexane) gave 34 mg of the title compound as the fastereluting isomer.

Step D.2-(4-chlorophenyl)-4-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,trifluoroacetic acid salt

The compound from Step C (34 mg) in 3 mL of dichloromethane and 3 mL ofTFA was shaken and kept at ambient temperature for 45 min. The mixturewas concentrated under nitrogen and then in vacuo. Trituration withether gave 35 mg of the title compound as a white solid. LC-MS 314.0(M+1).

Step E.7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-2-(4-chlorophenyl)-4-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,trifluoroacetic acid salt

A mixture of 28 mg (0.09 mmol) of(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoicacid, 35 mg (0.082 mmol) of amine from Step D, 17 mg of EDC, 12 mg ofHOBt, and 0.075 mL of diisopropylethylamine in 1.0 mL of dichloromethanewas kept at ambient temperature for 18 h. The mixture was applieddirectly to a 5-g silica gel cartridge, which was then elutedsequentially with 20 and 35% ethyl acetate/hexane to give 36 mg of theBoc protected intermediate. This was treated with 3 mL of TFA in 6 mL ofdichloromethane for 1 h at ambient temperature. The mixture wasconcentrated under a stream of nitrogen and then in vacuo. The residuewas triturated with ether to give, after drying in vacuo, 40.5 mg of thetitle compound as a white solid. LC-MS 510.9 (M+1).

EXAMPLE 8

7-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-2-(trifluoromethyl)-8-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,hydrochloride Step A. Ethyl 1,2-dibenzyl-3-oxopiperidine-4-carboxylate

To a solution of 3.7 mL (26.6 mmol) of diisopropylethylamine in 55 mL ofdry THF at −78° C. was added dropwise n-butyllithium (25 mmol, 10.0 mLof a 2.5 M solution in hexanes). The bath was replaced with an ice-waterbath. After 20 min, the mixture was recooled to −78° C. and 3.10 g(11.86 mmol) of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate in amixture of 20 mL of THF and 4.4 mL (24.4 mmol) of HMPA was addeddropwise. After 2 h, 1.47 mL (12.4 mmol) of benzyl bromide was addeddropwise, and the resultant mixture was allowed to warm slowly toambient temperature overnight. The reaction was then quenched by theaddition of 5 mL of saturated aqueous ammonium chloride solution. THFwas removed in vacuo, and the residue was partitioned between ether andwater. The organic phase was washed with 2 portions of brine andconcentrated to give a red oil. Purification by Biotage chromatography(silica gel, 3% ethyl acetate/hexane) gave 1.96 g (47%) of the titlecompound as a light yellow mobile oil. LC-MS 352.1 (M+1).

Step B.7,8-Dibenzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol

A 3.4 mL aliquot of sodium ethoxide solution in ethanol, prepared from1.24 g of sodium and 23.6 mL of absolute ethanol, was treated with 1.00g (8.93 mmol) of trifluoroacetamidine in 3 mL of absolute ethanolfollowed by 1.06 g (3.01 mmol) of ketoester from Step A in 8 mL ofabsolute ethanol. The reaction mixture was stirred at ambienttemperature for 15 min, then warmed at 87° C. in a sealed tube. After 18h, the reaction was cooled, and an additional 3.4 mL of the sodiumethoxide solution and 1.00 g of trifluoroacetamidine were added. Themixture was heated at 87° C. for an additional 24-h period, then cooledand concentrated. The residue was partitioned between ether and 0.5 Naqueous sodium hydroxide solution. The aqueous phase was extracted withether and then acidified with concentrated hydrochloric acid andextracted with ether. All the ether extracts were combined, washed withbrine, and concentrated to give 1.73 g of a yellow semisolid.Purification by flash chromatography (silica gel, 3.5%methanol/dichloromethane) gave 1012 mg (84%) of a yellow solid.Trituration with methanol gave 784 mg of the title compound as a brightyellow solid. LC-MS 400.2 (M+1).

Step C.7,8-Dibenzyl-4-chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A mixture of 669 mg (1.68 mmol) of7,8-dibenzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-oland 1.2 mL of phenylphosphonic dichloride was heated in a sealed tube at150° C. for 2.5 h. The mixture was cooled to ˜100° C., then poured intocrushed ice, washing with ethyl acetate. The resultant biphasic mixturewas neutralized with solid sodium bicarbonate to ˜pH 8 with vigorousstirring. The ethyl acetate layer was removed. The aqueous layer wasextracted with ethyl acetate. The combined organic phases were washedsequentially with saturated aqueous sodium bicarbonate solution andbrine, dried, and concentrated to give a red, viscous oil. Purificationby Biotage chromatography (silica gel, 5% ethyl acetate/hexane) gave 464mg (66%) of the title compound as a yellow solid. LC-MS 418.0 (M+1).

Step D.8-Benzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,hydrochloride

A mixture of 420 mg (1.005 mmol) of7,8-dibenzyl-4-chloro-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinefrom Step C and 63 mg of 10% palladium on carbon in 4 mL of ethylacetate and 7 mL of methanol was stirred under an atmosphere of hydrogenfor 2 h. The mixture was filtered through a 0.45 micron syringe filter,washing with methanol, and concentrated to give a white solid.Trituration with ether gave 330 mg (100%) of the title compound as awhite powder. LC-MS 294.1 (M+1).

Step E.7-[(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-2-(trifluoromethyl)-8-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A mixture of 133 mg (0.40 mmol) of(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoicacid and 162 mg (0.50 mmol) of8-benzyl-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,hydrochloride in 1.5 mL of acetonitrile at 0° C. was treatedsequentially with 81 mg (0.42 mmol) of EDC and 0.047 mL (0.42 mmol) ofN-methyl morpholine. After 10 min, the mixture was warmed to ambienttemperature and stirred for 3 h, then partitioned between 10 mL of ethylacetate and 4 mL of water. The organic layer was washed sequentiallywith saturated aqueous sodium bicarbonate solution and brine, dried andconcentrated to give 281 mg of the title compound as a mixture ofdiastereomers. Purification by flash chromatography (silica gel, 10 to35% ethyl acetate/hexane) followed by HPLC on a Chiralpak AD column (9%ethanol/hexane) gave 51 mg of the faster eluting isomer and 47 mg of theslower eluting isomer.

Step F.7-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-2-(trifluoromethyl)-8-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,hydrochloride

The individual isomers from Step D (25 mg and 29 mg, respectively) weretreated separately with 4 M hydrogen chloride solution in dioxane atambient temperature for 2 h. Concentration under nitrogen, then invacuo, followed by trituration with ether and drying gave 21.6 and 30.5mg, respectively, of the title compound as two individual diastereomers.LC-MS 509.1 (M+1) and 509.1 (M+H), respectively.

EXAMPLE 9

7-[(3R)-3-Amino-4-(2-hydroxy-5-fluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,trifluoroacetic acid salt Step A.7-[(3R)-3-[(1,1-Dimethylethoxycarbonyl)amino]-4-(2-benzyloxy-5-fluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

A mixture of 363 mg (0.9 mmol) of(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2-benzyloxy-5-fluorophenyl)butanoicacid, 72 mg (0.3 mmol) of2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinehydrochloride, 0.174 mL (1.0 mmol) of diisopropylethylamine, 136 mg (1.0mmol) of 1-hydroxy-7-azabenzotriazole (HOAT) and 380 mg (1.0 mmol) ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in 5 mL of dichloromethane was stirred underan atmosphere of nitrogen overnight. The reaction mixture was dilutedwith 100 mL of ethyl acetate, washed sequentially with 5% hydrochloricacid, saturated aqueous sodium bicarbonate solution, and brine, driedover magnesium sulfate, and concentrated. Purification by preparativeTLC (silica gel, 70% ethyl acetate/hexane) gave 152 mg (86%) of thetitle compound.

Step B.7-[(3R)-3-Amino-4-(2-hydroxy-5-fluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine,trifluoroacetic acid salt

A 38.3 mg (0.1 mmol) portion of BOC protected benzyl ether from Step Ain 5:2:1 ethyl acetate/methanol/dichloromethane was stirred overpalladium hydroxide under an atmosphere of hydrogen for 1.5 h. Themixture was filtered through a pad of Celite and concentrated to givethe BOC protected phenol, which was treated with 1:1 TFA/dichloromethanefor 1 h. Concentration and purification by HPLC (YMC C18 Pro column,gradient elution, 10–90% MeCN:H₂O containing 0.1% TFA) gave the titlecompound. LC-MS 399.3 (M+1).

Essentially following the procedures outlined for Examples 1–9, thecompounds listed of Table 2 were prepared.

TABLE 2

Ex. R¹ R² R³ R⁵ MS (M + 1) 10 CF₃ H 2-F, 5-F H 401.0 11 CF₃ H 2-F, 5-ClH 417.1 12 CF₃ H 2-Cl, 5-Cl H 435.4 13 CF₃ H 2-Me, 5-Cl H 413.4 14 CF₃OCHMe₂ 2-F, 5-F H 459.1 15 CF₃ NHMe 2-F, 5-F H 430.2 16 CF₃ H 2-F, 3-Cl,6-F H 435.2 17 4-CF₃-Ph OH 2-F, 5-F H 493 18 4-CF₃-Ph H 2-F, 5-F H 477.119 CF₃ H 3-Cl, 4-F H 417.2 20 CF₃ H 2-F, 4-Cl, 5-F H 435.0 21 4-F-Ph H2-F, 5-F H 427 22 CF₃ H 2-F, 3-F, 6-F H 419.2 23 CF₃ H 2-F, 4-F, 6-F H419.2 24 H H 2-F, 5-F H 333 25 3-Pyridyl H 2-F, 5-F H 410.0 26 Me H 2-F,5-F H 347 27 3-F-Ph H 2-F, 5-F H 427 28 Ph H 2-F, 5-F H 409 29 NMe₂ H2-F, 5-F H 376 30 4-morpholino H 2-F, 5-F H 418 31 4-OCF₃-Ph H 2-F, 5-FH 493 32 Cyclopropyl H 2-F, 5-F H 373 33 4-NMe₂-Ph H 2-F, 5-F H 452 344-pyridyl H 2-F, 5-F H 410 35 4-SO₂Me-Ph H 2-F, 5-F H 487 36 3-Me-4-NO₂-H 2-F, 5-F H 458 imidazol-2-yl 37 4-SO₂CF₃-Ph H 2-F, 5-F H 541 38Cyclopropyl H 2-F, 4-F, 5-F H 391 39 4-SO₂NH₂-Ph H 2-F, 5-F H 488 40NHCH₂Ph H 2-F, 5-F H 438.1 41 2-pyrazinyl H 2-F, 5-F H 411 42 CF₃ H 2-F,4-F, 5-F Me 433 43 4-Me-Ph H 2-F, 5-F H 423 44 3-Cl, 4-Cl-Ph H 2-F, 5-FH 477 45 4-SO₂Me-Ph H 2-F, 4-F, 5-F H 505 46 CF₃ H 2-F, 5-F Me 415 474-Cl-Ph H 2-F, 5-F H 443 48 2-Cl-Ph H 2-F, 5-F H 443 49 2-F-Ph H 2-F,5-F H 427 50 2-pyridyl H 2-F, 5-F H 410 51 4-CONH₂-Ph CF₃ 2-F, 5-F H520.1 52 2-pyrazinyl CF₃ 2-F, 5-F H 479.0 53 4-NH₂-Ph H 2-F, 5-F H 42454 H CF₃ 2-F, 5-F H 401.1 55 4-SO₂Me-Ph CF₃ 2-F, 5-F H 555.1 564-SO₂Me-Ph CF₃ 2-F, 4-F, 5-F H 573.0 57 4-NHSO₂Me- H 2-F, 5-F H 502 Ph

EXAMPLE OF A PHARMACEUTICAL FORMULATION

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any of the compounds of thepresent invention, 268 mg microcrystalline cellulose, 20 mg ofcroscarmellose sodium, and 4 mg of magnesium stearate. The active,microcrystalline cellulose, and croscarmellose are blended first. Themixture is then lubricated by magnesium stearate and pressed intotablets.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above. The specificpharmacological responses observed may vary according to and dependingupon the particular active compounds selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

1. A compound of the formula I:

wherein: Ar is phenyl which is unsubstituted or substituted with 1–5 ofR³, wherein R³ is independently selected from the group consisting of:(1) halogen, (2) C₁₋₆alkyl, which is linear or branched and isunsubstituted or substituted with 1–5 halogens, (3) OC₁₋₆alkyl, which islinear or branched and is unsubstituted or substituted with 1–5halogens, (4) CN, and (5) OH; R¹ and R² are independently selected fromthe group consisting of: (1) hydrogen, (2) CN, (3) C₁₋₁₀alkyl, which islinear or branched and which is unsubstituted or substituted with: (a)halogen, or (b) phenyl, which is unsubstituted or substituted with 1–5substituents independently selected from halogen, CN, OH, R⁴, OR⁴,NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁷R⁸, NR⁷R⁸, CONR⁷R⁸, CO₂H, andCO₂C₁₋₆alkyl, wherein the C₁₋₆alkyl is linear or branched, (4) phenylwhich is unsubstituted or substituted with 1–5 substituentsindependently selected from halogen, CN, OH, R⁴, OR⁴, NHSO₂R⁴,N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁷R⁸, NR⁷R⁸, CONR⁷R⁸, CO₂H, andCO₂C₁₋₆alkyl, wherein the C₁₋₆alkyl is linear or branched, (5) a 5- or6-membered heterocycle which may be saturated or unsaturated comprising1–4 heteroatoms independently selected from N, S and O, the heterocyclebeing unsubstituted or substituted with 1–3 substituents independentlyselected from oxo, halogen, NO₂, CN, OH, R⁴, OR⁴, NHSO₂R⁴,N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁷R⁸, NR⁷R⁸, CONR⁷R⁸, CO₂H, andCO₂C₁₋₆alkyl, wherein the C₁₋₆alkyl is linear or branched, (6)C₃₋₆cycloalkyl, which is optionally substituted with 1–5 substituentsindependently selected from halogen, OH, C₁₋₆alkyl, and OC₁₋₆alkyl,wherein the C₁₋₆alkyl and OC₁₋₆alkyl are linear or branched andoptionally substituted with 1–5 halogens, (7) OH, (8) OR⁴, and (9)NR⁷R⁸; R⁴ is C₁₋₆alkyl, which is linear or branched and which isunsubstituted or substituted with 1–5 groups independently selected fromhalogen, CO₂H, and CO₂C₁₋₆alkyl, wherein the C₁₋₆alkyl is linear orbranched; R⁵, R⁶ and R⁹ are independently selected from the groupconsisting of: (1) hydrogen, (2) C₁₋₁₀alkyl, which is linear or branchedand which is unsubstituted or substituted with one or more substituentsselected from: (a) halogen, (b) hydroxy, (c) phenyl, which isunsubstituted or substituted with 1–5 substituents independentlyselected from halogen, OH, C₁₋₆alkyl, and OC₁₋₆alkyl, wherein theC₁₋₆alkyl is linear or branched and optionally substituted with 1–5halogens, (d) naphthyl, wherein the naphthyl is optionally substitutedwith 1–5 substituents independently selected from halogen, OH,C₁₋₆alkyl, and OC₁₋₆alkyl, wherein the C₁₋₆alkyl is linear or branchedand optionally substituted with 1–5 halogens, (e) CO₂H, (f)CO₂C₁₋₆alkyl, (g) CONR⁷R⁸, (3) CN, (4) phenyl which is unsubstituted orsubstituted with 1–5 substituents independently selected from C₁₋₆alkyl,OC₁₋₆alkyl, hydroxy and halogen, wherein the C₁₋₆alkyl is linear orbranched and optionally substituted with 1–5 halogens, (5) naphthylwhich is unsubstituted or substituted with 1–5 substituentsindependently selected from C₁₋₆alkyl, OC₁₋₆alkyl, hydroxy and halogen,wherein the C₁₋₆alkyl is linear or branched and optionally substitutedwith 1–5 halogens, (6) CO₂H, (7) CO₂C₁₋₆alkyl, (8) CONR⁷R⁸, and (9)C₃₋₆cycloalkyl, which is unsubstituted or substituted with 1–5substituents independently selected from halogen, OH, C₁₋₆alkyl, andOC₁₋₆alkyl, wherein the C₁₋₆alkyl is linear or branched and optionallysubstituted with 1–5 halogens; R⁷ and R⁸ are independently selected fromthe group consisting of: (1) hydrogen, (2) phenyl, which isunsubstituted or substituted with substituents independently selectedfrom halogen, OH, C₁₋₆alkyl, and OC₁₋₆alkyl, wherein the C₁₋₆alkyl islinear or branched and optionally substituted with 1–5 halogens, (3)C₃₋₆cycloalkyl, which is unsubstituted or substituted with substituentsindependently selected from halogen, OH, C₁₋₆alkyl, and OC₁₋₆alkyl,wherein the C₁₋₆alkyl is linear or branched and optionally substitutedwith 1–5 halogens, and (4) C₁₋₆alkyl, which is linear or branched andwhich is unsubstituted or substituted with: (a) halogen, or (b) phenyl,which is unsubstituted or substituted with 1–5 substituentsindependently selected from halogen, OH, C₁₋₆alkyl, and OC₁₋₆alkyl,wherein the C₁₋₆alkyl is linear or branched and optionally substitutedwith 1–5 halogens, or wherein R⁷ and R⁸ together with the nitrogen atomto which they are attached form a heterocyclic ring selected fromazetidine, pyrrolidine, piperidine, piperazine, and morpholine whereinsaid heterocyclic ring is unsubstituted or substituted with one to fivesubstituents independently selected from halogen, hydroxy, C₁₋₆ alkyl,and C₁₋₆ alkoxy, wherein alkyl and alkoxy are unsubstituted orsubstituted with one to five halogens; or a pharmaceutically acceptablesalt thereof or an individual diastereomer thereof.
 2. The compound ofclaim 1 of the formula Ia:

wherein Ar, R¹, R², R⁵, R⁶ and R⁹ are defined in claim 1; or apharmaceutically acceptable salt thereof or an individual diastereomerthereof.
 3. The compound of claim 1 of the formula Ib:

wherein Ar, R¹, R² and R⁵ are defined in claim 1; or a pharmaceuticallyacceptable salt thereof or an individual diastereomer thereof.
 4. Thecompound of claim 1 of the formula Ic:

wherein Ar, R¹ and R⁵ are defined in claim 1; or a pharmaceuticallyacceptable salt thereof or an individual diastereomer thereof.
 5. Thecompound of claim 1 of the formula Id:

wherein Ar and R¹ are defined in claim 1; or a pharmaceuticallyacceptable salt thereof or an individual diastereomer thereof.
 6. Thecompound of claim 1 of the formula Ie:

wherein Ar, R¹ and R² are defined in claim 1; or a pharmaceuticallyacceptable salt thereof or an individual diastereomer thereof.
 7. Thecompound of claim 1 wherein Ar is phenyl which is unsubstituted orsubstituted with 1–5 of R³ which are independently selected from thegroup consisting of: (1) fluoro, (2) chloro, (3) bromo, (4) methyl, (5)CF₃, and (6) OH.
 8. The compound of claim 1 wherein Ar is selected fromthe group consisting of: (1) phenyl, (2) 2-fluorophenyl, (3)3,4-difluorophenyl, (4) 2,5-difluorophenyl, and (5)2,4,5-trifluorophenyl.
 9. The compound of claim 1 wherein R¹ is selectedfrom the group consisting of: (1) hydrogen, (2) C₁₋₆alkyl, which islinear or branched and which is unsubstituted or substituted with phenylor 1–5 fluoro, (3) phenyl which is unsubstituted or substituted with 1–5substituents independently selected from halogen, CN, OH, R⁴, OR⁴,NHSO₂R⁴, N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁷R⁸, NR⁷R⁸, CONR⁷R⁸, CO₂H, andCO₂C₁₋₆alkyl, wherein the C₁₋₆alkyl is linear or branched, (4) a 5- or6-membered heterocycle which may be saturated or unsaturated comprising1–4 heteroatoms independently selected from N, S and O, the heterocyclebeing unsubstituted or substituted with 1–3 substituents independentlyselected from oxo, halogen, NO₂, CN, OH, R⁴, OR⁴, NHSO₂R⁴,N(C₁₋₆alkyl)SO₂R⁴, SO₂R⁴, SO₂NR⁷R⁸, NR⁷R⁸, CONR⁷R⁸, CO₂H, andCO₂C₁₋₆alkyl, wherein the C₁₋₆alkyl is linear or branched, (5)C₃₋₆cycloalkyl, and (6) NR⁷R⁸.
 10. The compound of claim 1 wherein R¹ isselected from the group consisting of: (1) hydrogen, (2) CF₃, (3) phenylwhich is unsubstituted or substituted with 1–5 substituentsindependently selected from halogen, methyl, CF₃, OCF₃, NHSO₂Me,NHSO₂CF₃, SO₂Me, SO₂CF₃, SO₂NH₂, NH₂, NHMe, NMe₂, and CONH₂, (4)pyridine, pyrazine, and imidazole which is unsubstituted or substitutedwith 1–5 substituents independently selected from CF₃, Me, and NO₂, (5)cyclopropyl, (6) morpholine, (7) NH₂, (8) NHMe, (9) NMe₂, and (10)NHCH₂Ph.
 11. The compound of claim 1 wherein R¹ is selected from thegroup consisting of: (1) hydrogen, (2) CF₃, (3) phenyl which isunsubstituted or substituted with 1–5 substituents independentlyselected from halogen, methyl, CF₃, OCF₃, NHSO₂Me, SO₂Me, SO₂CF₃,SO₂NH₂, and CONH₂, (4) pyridine, pyrazine, or imidazole which isunsubstituted or substituted with 1–5 substituents independentlyselected from CF₃, Me, and NO₂, and (5) cyclopropyl.
 12. The compound ofclaim 1 wherein R¹ is hydrogen or CF₃.
 13. The compound of claim 1wherein R² is selected from the group consisting of: (1) hydrogen, (2)C₁₋₆alkyl, which is linear or branched and which is unsubstituted orsubstituted with 1–5 fluoro, (3) OH, (4) OR⁴, and (5) NR⁷R⁸.
 14. Thecompound of claim 1 wherein R² is selected from the group consisting of:(1) hydrogen, (2) OH, (3) methoxy, (4) isopropoxy, (5) CF₃, (6) NH₂, and(7) NHMe.
 15. The compound of claim 1 wherein R² is hydrogen.
 16. Thecompound of claim 1 wherein R⁵, R⁶ and R⁹ are independently selectedfrom the group consisting of: (1) hydrogen, and (2) C₁₋₁₀alkyl, which islinear or branched and which is unsubstituted or substituted with one ormore substituents selected from: (a) halogen, and (b) phenyl, whereinthe phenyl is optionally substituted with 1–5 substituents independentlyselected from halogen, OH, C₁₋₆alkyl, and OC₁₋₆alkyl, wherein theC₁₋₆alkyl and OC₁₋₆alkyl are linear or branched and optionallysubstituted with 1–5 halogens.
 17. The compound of claim 1 wherein R⁵,R⁶ and R⁹ are independently selected from the group consisting of: (1)hydrogen, (2) CH₃, and (3) CH₂-phenyl.
 18. The compound of claim 1wherein R⁵ is H or CH₃ and R⁶ and R⁹ are hydrogen.
 19. A compound whichis selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1.21. A method of treating Type II diabetes comprising administering to amammalian patient in need of such treatment a therapeutically effectiveamount of a compound of claim 1.